Yokobori and Yokota Journal of Intensive Care (2016)

4:28 DOI 10.1186/s40560-016-0137-4

REVIEW Open Access

Targeted temperature management

in traumatic brain injury
Shoji Yokobori* and Hiroyuki Yokota

Abstract
Traumatic brain injury (TBI) is recognized as the significant cause of mortality and morbidity in the world. To
reduce unfavorable outcome in TBI patients, many researches have made much efforts for the innovation of
TBI treatment. With the results from several basic and clinical studies, targeted temperature management
(TTM) including therapeutic hypothermia (TH) have been recognized as the candidate of neuroprotective
treatment. However, their evidences are not yet proven in larger randomized controlled trials (RCTs). The main
aim of this review is thus to clarify specific pathophysiology which TTM will be effective in TBI.
Historically, there were several clinical trials which compare TH and normothermia. Recently, two RCTs were able
to demonstrate the significant beneficial effects of TTM in one specific pathology, patients with mass evacuated
lesions. These suggested that TTM might be effective especially for the ischemic-reperfusional pathophysiology of
TBI, like as acute subdural hematoma which needs to be evacuated. Also, the latest preliminary report of
European multicenter trial suggested the promising efficacy of reduction of intracranial pressure in TBI.
Conclusively, TTM is still in the center of neuroprotective treatments in TBI. This therapy is expected
to mitigate ischemic and reperfusional pathophysiology and to reduce intracranial pressure in TBI.
Further results from ongoing clinical RCTs are waited.
Keywords: Targeted temperature management, Therapeutic hypothermia, Traumatic brain
injury, Ischemia, Reperfusion, Intracranial pressure

Introduction management of TBI and neurointensive care to prevent

In the USA, an estimated 1.4 million people still suffer a additional secondary brain injury.
traumatic brain injury (TBI) each year [1]. About 50,000 To mitigate the secondary brain injury in TBI patients,
people die before the hospital, and at least 5.3 million live many basic and clinical researches have been performed
with severe disabilities related to TBI [2]. TBI thus has for the innovation of pharmacological treatments and
been a significant and growing public health issue. temperature managements [3, 5–7].
The most important factor which determines the prog- With the results of numerous previous basic research
nosis of TBI patients is the severity of the primary brain and clinical trials, targeted temperature management
injury [3]. Additional delayed secondary brain damage is (TTM) including therapeutic hypothermia (TH) has been
set in progress and continues from the time of traumatic recognized as the candidate of neuroprotective treatment
impact in TBI patients, and the two combine to deter- in the neurocritical care [8, 9]. However, their clear
mine outcome [4]. evidences in TBI patients are not yet proven in large
Primary brain injury itself is mostly not amenable to randomized controlled trials (RCTs). TTM for TBI is thus
treatment; consequently, the strategy of primary TBI still limited to an optional recommendation (level 3 in
treatment should be prevention, such as use of helmets Brain Trauma Foundation guideline) [10].
and vehicle modification. Therefore, the main stream of The main aim of this review is to clarify specific
treatment strategy for TBI should be the surgical pathophysiology for which TTM will be most effective.
First, we will mention the general classification of patho-
* Correspondence: [email protected] physiology in TBI, and we then will discuss the specific
Department of Emergency and Critical Care Medicine, Nippon pathophysiology which will be most beneficial with
Medical School, 1-1-5, Sendagi, Bunkyo-Ku, Tokyo 113-8603, Japan

© 2016 Yokobori and Yokota. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Yokobori and Yokota Journal of Intensive Care (2016) 4:28 Page 2 of 10

TTM. In the latter part of this review, we will focus on the [13]. This distinction has now evolved to consider the
appropriate timing, length, and the rewarming rate of pathological mechanisms imparted by the trauma in
TTM in TBI patients. regions local to and remote from the point of impact.
Although these classifications are widely accepted, most
Review TBIs consist of a heterogeneous admixture of focal and
Definition of “Targeted temperature management” and diffuse damage [12]. Focal and diffuse pathological pro-
“Therapeutic hypothermia” cesses are often intermingled, making it difficult to divide
To maintain normal physiology and to cure pathophysi- into focal, diffuse, and primary and secondary categories;
ology in critically ill patients, control of systematic body it is useful to consider them separately for the purpose of
temperature has been enlightened in neurocritical care understanding the pathophysiology (Table 1).
settings. However, several terms and definitions sur- For example, acute subdural hematoma (ASDH) is a
rounding therapeutic body temperature management have good representative of focal brain injury which also has
also been existed, like TTM, TH, and therapeutic the aspect of both of primary and secondary brain in-
normothermia. In a review of Polderman, “hypothermia” juries. In ASDH, neuropathologic study showed ische-mic
was proposed to be defined as the status of patients’ core brain damage in the hemisphere underlying the hematoma
temperature <36.0 °C regardless of the cause. Also, “in- [14]. An important factor leading to this ischemic damage
duced hypothermia” was defined as “intentional reduc-tion is raised intracranial pressure (ICP) producing impaired
of a patients’ core temperature below 36.0 °C”. Further, cerebral perfusion. Increasing ICP reduces the volume of
TH was defined as “Controlled induced hypothermia with cerebral blood circulation. Re-moval of the hemorrhage
the potentially deleterious effects such as shivering, being may result in the immediate reversal of global ischemia.
controlled or suppressed” [5]. On the other hand, TTM is And this abrupt reduction of mass lesion sometimes
widely including the concept of TH and therapeutic induces secondary “reperfusion injury” [14–16]. Previous
normothermia therapy. A recent report recommends that experimental and clinical studies thus have shown that
the term “Targeted temperature man-agement” should subdural hematoma and its removal was considered as an
replace “therapeutic hypothermia” [11]. In this report ischemic/reperfusion (I/R) patho-physiology in TBI [17,
which was published from professional so-cieties 18].
including the Society of Critical Care Medicine, the term
“therapeutic hypothermia” was discarded in favor of TTM History and future direction of TTM for TBI
with emphasizing the importance of defin-ing a complete Historically, TTM were induced prior to surgery to assist
temperature profile [11]. According to this procedures that caused prolonged ischemia, including
recommendation, we also generally define and use the open heart surgery [19, 20] and various organ transplants
term “TTM” which means temperature management [21]. Within its first decade, hypothermia was applied to
therapy including both of TH and therapeutic normo- multiple emergency situations that were characterized by
thermia therapy in this review. ischemia such as stroke [22, 23], myocardial infarction
[24], and cardiac arrest [25, 26].
Pathophysiology of TBI As we mentioned previously, basic and clinical studies
As mentioned above, the pathophysiology of TBI is relating the effectiveness of TTM on the neuroprotective
mainly divided as primary and secondary brain injuries effect was also reported in TBI patients [27–29]. In 2001,
[12]. Both primary and secondary brain injuries can be a larger multicenter trial of hypothermia for neu-
further classified by focal or diffuse mechanisms (Table roprotection in TBI was reported [30] (Table 2). In this
1). The distinction of focal and diffuse injuries is RCT, 392 patients with acute brain injury were random-
historically derived from the absence or presence of ized to normothermia or surface cooling-induced
radiographic mass lesions on computed tomography hypothermia. Contrary to the previous phase 2 trial [27],

Table 1 Type and pathophysiology of traumatic brain injury

Diffuse brain injury Focal brain injury
Primary brain injury • Diffuse axonal injury • Focal cortical contusion
• Petechial white matter hemorrhage with diffuse vascular injury • Intracerebral hemorrhage
• Extracerebral hemorrhage (i.e., ASDH, AEDH)
Secondary brain injury • Delayed neuronal injury • Delayed neuronal injury
• Diffuse brain swelling • Focal brain swelling
• Diffuse ischemic injury • Focal ischemic injury
• Diffuse hypoxic injury • Focal hypoxic injury
• Diffuse metabolic dysfunction • Regional metabolic dysfunction
ASDH acute subdural hematoma, AEDH acute epidural hematoma
 Yokobori and Yokota Journal of Intensive Care (2016) 4:28
Table 2 Recent randomized clinical trials (RCTs) relating TTM on TBI
RCTs Age No. of Type of TBI Control temperature Time interval of Rewarming Neurologic outcome Mortality Comments/references
(years old) patients temperature control speed
NABIS:H 16–65 392 All, severe 33 °C vs 37 °C 48 h 0.5 °C/2 h 57 % poor outcome in 28 % TH vs 27 % Clifton et al. [30]
each group, NS Normo, NS
Weak evidence of improved
outcomes in patients who
were initially hypothermic
on admission
NABIS:H II 16–45 97 All, severe, 2.5 h after 33 °C vs 37 °C 48 h 0.5 °C/2 h 60 % TH 57 % Normo, 23 % TH vs 18 % Clifton et al. [30]
suffering TBI NS Normo NS
Early-induced hypothermia
proved significantly
efficacious for surgically
evacuated hematoma
B-HYPO 15–70 148 All 32-34 °C vs 35.5–37 °C >72 h and <1 °C/day Relative risk (RR) 1.24, (RR 1.82, 95 % CI Maekawa et al. [33]
95 % confidence 0.82–4.03, p =
Clinical Trial gov.
interval (CI) 0.62–2.48, 0.180) NS
p = 0.597, NS NCT00134472 UMIN
000000231
EUROTHERM −65 1800 Primary closed TBI 32-35 °C vs Normo 48 h continued for as NM – – Andrews et al. [89]
3235 with raised ICP long as is necessary
>20 mmHg to reduce and maintain
ICP <20 mmHg
LTH-1 18–65 300 All, GCS4-8 Longer TH (34–35 °C) for 5 days <0.5 °C/4 h – – Lei et al. [62]
5 days vs Normo (36–
ClinicalTrials.gov Identifier:
37 °C).
NCT01886222
HOPES 21–65 120 ASDH with 33 °C vs 37 °C 48 h 0.1 °C/h – – ClinicalTrials.gov
Evacuated (GCSM Preoperative induction NCT02064959 and UMIN
<6) 000014863
TBI traumatic brain injury, TH therapeutic hypothermia, NS not significant, Normo normothermia, NM not mentioned

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Yokobori and Yokota Journal of Intensive Care (2016) 4:28 Page 4 of 10

this study could not prove the efficacy of hypothermia in improves the outcome following TBI with ASDH requir-ing
TBI. However, there was a weak evidence of improved evacuation. The primary objective is to determine if rapid
outcomes in patients who were initially hypothermic on induction of hypothermia prior to emergent craniot-omy for
admission and treated with continued hypothermia for 24 ASDH will improve the outcome as measured by Glasgow
h [30]. This same study group then tried to confirm the Outcome Scale-Extended (GOSE) at 6 months. Over 120
efficacy of very early hypothermia in patients with severe ASDH patients will be registered by 2018 (ClinicalTrials.gov
brain injury, the National Acute Brain Injury NCT02064959 and UMIN 000014863).
Study:Hypothermia II (NABIS:H II) [31]. In this NAB-
IS:H II, the early-induced hypothermia did not have effi- The mechanisms of I/R brain injury and hypothermia
cacy when mortality and morbidity data were looked at. treatment
On the other hand, in a sub-populational analysis divid- Despite much research, the exact mechanisms of the I/R
ing the patients into those with diffuse brain injury and injury itself remain unclear. Reperfusion following ische-mia
those with surgical hematoma evacuation, early-induced can cause neurovascular injury leading to detrimental
hypothermia proved significantly efficacious for the lat- changes in the blood-brain barrier (BBB) permeability,
ter group [31]. Authors concluded that one explanation cerebral edema, brain hemorrhage, and neuronal death by
was the different pathophysiology between diffuse brain apoptosis/necrosis [35]. These complications clearly limit the
injury and hematoma. These results suggested the efficacy benefits of reperfusional therapies. The processes lead-ing to
of TTM especially in focal brain injury which received cellular damage after I/R injury are complex and
hematoma evacuation and which had the I/R multifactorial. At this point, the pathology of I/R injury has
pathophysiology. been separated into two distinct mechanisms. One is the cell
The efficacy of early-induced therapeutic hypothermia death following cellular dysfunction, i.e., excito-toxicity,
was also proved in animal experimental TBI model. With acidotoxicity, and ionic imbalance. This first process is seen
considering the data of NABIS:H II, we also hypoth- primarily in the ischemic phase. The other type of injury
esized that preoperatively early induced hypothermia comes from free radical production, and this becomes
maybe beneficial to mitigate reperfusional injury occurred particularly bad during the reperfusion phase
by craniotomy and clot removal in ASDH rat model [32]. [36]. Together, these mechanisms create a complicated
Our data suggested that early, preoperatively induced picture of injury (Fig. 1). In the ischemic phase, brain is-
hypothermia could mediate the reduction of neuronal and chemia initiates a cascade of destructive and often irre-
glial damage in the reperfusion phase of I/R TBI [32]. versible processes that destroy brain cells and tissue. One
More recently, Maekawa et al. compared prolonged example of this is the intracellular conversion to anaerobic
mild TH versus fever control with tight hemodynamic metabolism [37]. Depletion of adenosine triphosphate
monitoring and slow rewarming in patients with severe (ATP) in the absence of oxidative metabolism leads to failure
traumatic brain injury with a multicenter RCT (B-HYPO) of the Na+/K+ ATPase pump. This causes depolarization of
in patients with severe TBI [33] (Table 2). Patients were the cell membrane leading to activation of voltage-gated
assigned to either therapeutic hypothermia (32–34 °C) or calcium channels and an influx of intra-cellular calcium [38].
fever control (35.5–37 °C). Patients with therapeutic Moreover, with the anaerobic metab-olism induced,
hypothermia were cooled as soon as possible for ≥72 h intracellular and extracellular acidosis contributes to the
and rewarmed at a rate of <1 °C/day. There were no sig- calcium influx. This rapid increase in intracellular calcium
nificant differences in the likelihood of poor neurological causes release of large amounts of the excitatory
outcome or mortality between the two groups. However, neurotransmitter glutamate, which further stimulates calcium
one subanalysis of this study showed the efficacy of influx in postsynaptic cells [39]. In addition to the above,
hypothermia especially for young TBI patients who had calcium triggers activation of phospholipase, nitric oxide
focal hematoma which needed evacuation [34]. synthase, proteases, endonu-cleases, and oxidase enzymes
Conclusively, large RCTs still have not yet shown the [40]. These activated mole-cules can easily damage other cell
efficacy of TTM in TBI treatment (Table 2). However, proteins and lipid membranes causing necrosis [41].
subanalysis of RCTs and animal experimental research Furthermore, recent studies have demonstrated the
showed that early, preoperatively induced hypothermia production of superoxide radicals by N-methyl-D-aspartate
may mediate the reduction of neuronal and glial damage (NMDA) receptor-mediated nicotinamide adenine
in the reperfusion phase of focal brain injury which has dinucleotide phosphate (NADPH) oxidase activation [42].
I/R pathophysiology [4]. Such events amplify reactive oxygen species (ROS)
Now, an international multicenter RCT (HOPES Trial) production, mitochon-drial dysfunction, and proapoptotic
is currently in progress. In this trial, nine Japanese centers protein activation. Intracellular calcium accumulation itself
and three centers in the USA are included as participants. also triggers initiation of mitochondrial dysfunction and
The objective of this trial is to test whether hypothermia fragmentation
Yokobori and Yokota Journal of Intensive Care (2016) 4:28 Page 5 of 10

Fig. 1 The schema of mechanisms of ischemic/reperfusional (I/R) brain injury and the effective point of hypothermia treatment. The pathology
of I/R injury is approximately separated as two mechanisms, i.e., the cell death following cellular dysfunction in ischemic phase and the free
radical production in reperfusion phase. The boxed arrow with entered “Hypothermia” means the estimated effective points in I/R cascade

leading to activation of proapoptotic proteins such as the How soon is the induction of TTM in order to be
caspases [43]. beneficial for brain injury?
Reperfusion to this ischemic tissue results in a short The previous studies have shown that hypothermia must
period of excessive free radical production [44]. Experi- be achieved within 2 to 6 h of severe hypoxic-ischemic
mental measurements of the reperfusion phase demon- injury in animal models. For example, cooling sheep to 34
strate that oxygen- and carbon-centered free radicals peak °C for 72 h gave good neuroprotection if started 90 min
within 5 min of reperfusion [45] and that hydroxyl after the injury. It was partly effective if started at 5.5 h
generation peaks within 15 min [46]. This oxidative stress and was ineffective if started at 8.5 h [56]. Most clinical
can damage proteins, lipids, and DNA, possibly leading to trials have suggested that the earlier mild hypothermia is
necrosis and apoptosis [47, 48]. Oxidants also modulate initiated, the more likely beneficial effects may be
neuroinflammation [49] leading to increased levels of obtained [30]. Hypothermia is currently being induced by
neuronal apoptosis in adjacent cells [50–52]. surface cooling with use of cooling blankets, which
Despite much basic and clinical research using usually requires 4 to 8 h to get the target hypothermia
hypothermia in I/R brain injury, the mechanisms of its temperature (33 to 35 °C) [30, 57–59].
neuronal protection remain unclear. Most believe it to act Bernard et al. reported that cooling can be achieved
through a multitude of different pathways. Mitochon-drial more rapidly (2 °C over 30 min) by intravenous adminis-
free radical production might be an important target, and it tration of iced (4 °C) crystalloid solution [59].
provides a possible window of opportunity for hypothermia Innovation of cooling device also enables rapid induc-
treatment. Supporting this point, hypothermia has been tion of TTM in TBI. Recently, the use of intravascular
shown to decrease abnormal production of free radicals [53]. cooling device was spreading in the scene of neurocriti-
Another potential mechanism of hypothermia involves cal care. This device is now also approved in Japan and
reduction of the inflammatory cascade and cell death widely started to use for TTM in neurocritical care pa-
pathways of apoptosis and necrosis [54]. tients. Several reports that compare intravascular cooling
Hypothermia also reduces cellular metabolism and to surface cooling exist. de Waard et al. compared the
oxygen demand while maintaining acceptable ATP levels intravascular cooling device and surface cooling device
[55]. Likewise, it improves cellular ion handling and cel- and concluded that time to reach target temperature and
lular pH balance [37]. In Fig. 1, we illustrate the schema cooling speeds was the same between two devices. And
of mechanisms of I/R injury and the estimated points the variation coefficient for temperature during
where hypothermia treatment can effect. maintenance was higher in the surface than that for the
Yokobori and Yokota Journal of Intensive Care (2016) 4:28 Page 6 of 10

intravascular cooling group (mean 0.85 % versus 0.35 %, and rewarming durations. All previous hypothermia
p < 0.0001) [60]. This use of cold intravenous fluids and studies describe no severe complications from the
new cooling devices may represent a logical strategy for perioperative-induced hypothermia. One should note that
future clinical trials for accurate TTM in severe TBI. their cooling and rewarming durations were all rela-tively
short (Table 3). Important consideration must be given, as
Therapeutic window for TTM several researchers have pointed out, to cooling rate,
There are still no clear evidences on the optimal length of period of hypothermia, rewarming rate, and volumes of
TTM in TBI. A recent experimental research showed that intravenous fluid [74–77].
persisting lower temperature significantly reduced the
synthesis of hypoxia-inducible factor 1 (HIF-1, a pro-tein Induced normothermia and avoiding hyperthermia in TBI:
relating hypoxic tolerance) under hypoxic conditions and is it effective?
weaken adaptation to hypoxia [61]. On the other hand, a Clinical studies that prove the efficacy of induced nor-
clinical research showed the efficacy of longer mothermia is much less than that of induced hypothermia.
hypothermia therapy for neuroprotection in TBI. Jiang et One study from Pittsburgh group showed the efficacy of
al. performed a single center randomized study to com- induced normothermia (fever prophylaxis with
pare the effect of long-term (5 days) mild hypothermia intravascular cooling catheter) with reduction of
versus short-term (2 days) mild hypothermia suggesting intracranial hypertension compared to control group
that mild hypothermia may improve the outcome in a [78]. More recently, Suehiro et al. reported the Japanese
series of 215 severe adult TBI patients, when cooling is survey of brain temperature management (TH, intensive
maintained for longer than 48 h [57]. More recently, a normothermia, and no temperature management) in pa-
multicenter RCT to examine the efficacy and safety of tients with traumatic brain injury [79]. In this survey, a
long-term mild hypothermia (34–35 °C for 5 days) in total number of 1091 patients were analyzed. Favorable
severe TBI is planned in China (the LTH-1 trial) [62]. outcome was significantly higher with TH group (52.4 %)
Rate of rewarming is also an important variable for compared to intensive normothermia (26.9 %) and no
influencing the protective effects of the hypothermia temperature management (20.7 %). This data suggested
therapy. In the experimental setting, posttraumatic that TTM is significantly effective for TBI management
hypothermia followed by slow rewarming appears to comparing to no temperature management.
provide maximal protection in terms of traumatically Several other studies showed that hyperthermia was
induced axonal damage, microvascular damage and dys- associated with a statistically significant increase in the
function, and contusional expansion [63, 64]. In contrast, increase of ICU stay, lower Glasgow coma scale score on
hypothermia followed by rapid rewarming not only re- discharge from ICU, and lower neurological function at 6
verses the protective effects associated with hypothermic months after initial injury [80, 81].
intervention but also, in many cases, exacerbates the Conclusively, appropriate thermoregulation with TTM
traumatically induced pathology and its functional (TH and intensive normothermia) is significantly im-
consequences [64–66]. portant in TBI. Indeed, these data have led to several
Conclusively, longer maintenance and slower rewarm- recommendations for and strict control of temperature in
ing may be beneficial in TBI. On the other hand, we also the neuro-ICU settings [82, 83].
need to be cautious for severe side effects of longer
hypothermia maintenance [37]. TTM for controlling intracranial hypertension in TBI
Raised ICP and intracranial hypertension are important
Preoperative-induced hypothermia for traumatic brain predictors of mortality in patients with severe TBI [84].
injury Aggressive treatment of elevated ICP has been shown to
As we mentioned above, recent clinical studies suggested reduce mortality and improve outcome [10, 85, 86]. TTM
that preoperatively early induced hypothermia maybe also has been a promising treatment strategy for
beneficial in focal mass TBI. However, we still cannot controlling intracranial pressure in TBI [87, 88].
find feasibility of pre- and intraoperatively induced To clarify the effect of TTM for the treatment of intra-
hypothermia especially for TBI. There are some reports cranial hypertension, the latest clinical trial (EURO-
that used intraoperative hypothermia in neurosurgical THERM 3235) is now ongoing [89] (Table 2). In this
procedures involving craniotomy (Table 3) [67–73]. trial, patient with refractory intracranial hypertension
These studies can teach us important lessons in planning (ICP > 20 mmHg) is assigned as TH group or control
future clinical trials using early-induced hypothermia in group (standard treatment without any TTM). Two
TBI. Specifically, we have learned that (1) perioperative- treatment groups are compared with mortality on the 28th
induced hypothermia is feasible and safe and (2) careful day after injury or on discharge. The sample size of this
consideration should be used in determining the cooling study is estimated as 600 patients. Recently,
 Yokobori and Yokota Journal of Intensive Care (2016) 4:28
Table 3 Clinical studies using intraoperative hypothermia for neurosurgical procedures
Authors and year No. of cases Operative procedure Cooling Complication Mean target Mean duration Mean rewarming Mean rewarming Effectiveness
(number) method temp (°C) of hypothermia rate(°C/h) temp (°C) of hypothermia
(min)
Baker et al., 30 (Normo Elective craniotomy for WB Shivering (Normo 0 34.3 ± 0.4 NR 0.7 ± 0.6 35.8 ± 1.0 NR
[67] 1994 17, Hypo13 ) supratentorial tumor case vs Hypo 7 cases,
resection (14), aneurysm p = 0.002). No severe
repair (14), other (2) comp.
Clifton and 21 Hypo Aneurysm surgery with WB No comp. 32.0 NR NR NR NR
Christensen, elective craniotomy (21)
[68] 1992
Hindman et al, 114 (Normo SAH clipping (52), AC No significant difference 33.7 (33.2– NR NR 35.7 (34.9–36.4) NS
[69] 1999 57, Hypo 57) unruptured aneurysm between Normo and 34.2)
clipping (62) Hypo. No severe comp.
Sato and 60 (Normo SAH clipping AC and WB NR 34.0 NR Time, 115 min 36.2 NR
Yoshimoto [70] 28, Hypo 32) (45–250 min)
2000
Steinberg et al., 153 Hypo Elective open craniotomy WB(61) vs Postoperative infection 33.0 274 1.88 (WB) vs 0.69 (35–36) NS between
[71] 2004 for unruptured cerebral endo(92) 4.3 % endo vs 4.9 % (endo) WB and endo
aneurysm WB, NS. No severe comp.
in all
Todd et al, [72] 1000 (Normo SAH clipping AC Postoperative bacteremia 33.0 (32.5– 324 ± 120 NR 36.4 ± 1.0 NS
2005 501, Hypo 499) (5 % Hypo vs 3 % Normo, 33.5)
P = 0.05, no severe comp.
in all.
Hindman et al., 441 (Normo SAH patients undergoing AC NR 33.3–0.8 NR Time, 120 min 36.7–0.5 NS
[73] 2010 233, Hypo 208) temporary clipping
Normo normothermia, Hypo hypothermia, SAH subarachnoidal hemorrhage, WB water blanket cooling, AC air cooling, endo endovascular cooling, comp complication, NA, not applicable, NR not
reported, NS not significant

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Acknowledgements techniques of some open intracardiac procedures under
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