Targeted temperature management in traumatic brain injury
© Yokobori and Yokota. 2016
Received: 2 July 2015
Accepted: 4 February 2016
Published: 27 April 2016
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.
In the USA, an estimated 1.4 million people still suffer a traumatic brain injury (TBI) each year . About 50,000 people die before the hospital, and at least 5.3 million live with severe disabilities related to TBI . TBI thus has been a significant and growing public health issue.
The most important factor which determines the prognosis of TBI patients is the severity of the primary brain injury . Additional delayed secondary brain damage is set in progress and continues from the time of traumatic impact in TBI patients, and the two combine to determine outcome .
Primary brain injury itself is mostly not amenable to treatment; consequently, the strategy of primary TBI treatment should be prevention, such as use of helmets and vehicle modification. Therefore, the main stream of treatment strategy for TBI should be the surgical management of TBI and neurointensive care to prevent additional secondary brain injury.
With the results of numerous previous basic research and clinical trials, targeted temperature management (TTM) including therapeutic hypothermia (TH) has been recognized as the candidate of neuroprotective treatment in the neurocritical care [8, 9]. However, their clear evidences in TBI patients are not yet proven in large randomized controlled trials (RCTs). TTM for TBI is thus still limited to an optional recommendation (level 3 in Brain Trauma Foundation guideline) .
The main aim of this review is to clarify specific pathophysiology for which TTM will be most effective. First, we will mention the general classification of pathophysiology in TBI, and we then will discuss the specific pathophysiology which will be most beneficial with TTM. In the latter part of this review, we will focus on the appropriate timing, length, and the rewarming rate of TTM in TBI patients.
Definition of “Targeted temperature management” and “Therapeutic hypothermia”
To maintain normal physiology and to cure pathophysiology in critically ill patients, control of systematic body temperature has been enlightened in neurocritical care settings. However, several terms and definitions surrounding therapeutic body temperature management have also been existed, like TTM, TH, and therapeutic normothermia. In a review of Polderman, “hypothermia” was proposed to be defined as the status of patients’ core temperature <36.0 °C regardless of the cause. Also, “induced hypothermia” was defined as “intentional reduction of a patients’ core temperature below 36.0 °C”. Further, TH was defined as “Controlled induced hypothermia with the potentially deleterious effects such as shivering, being controlled or suppressed” . On the other hand, TTM is widely including the concept of TH and therapeutic normothermia therapy. A recent report recommends that the term “Targeted temperature management” should replace “therapeutic hypothermia” . In this report which was published from professional societies including the Society of Critical Care Medicine, the term “therapeutic hypothermia” was discarded in favor of TTM with emphasizing the importance of defining a complete temperature profile . According to this recommendation, we also generally define and use the term “TTM” which means temperature management therapy including both of TH and therapeutic normothermia therapy in this review.
Pathophysiology of TBI
Type and pathophysiology of traumatic brain injury
Diffuse brain injury
Focal brain injury
Primary brain injury
• Diffuse axonal injury
• Petechial white matter hemorrhage with diffuse vascular injury
• Focal cortical contusion
• Intracerebral hemorrhage
• Extracerebral hemorrhage (i.e., ASDH, AEDH)
Secondary brain injury
• Delayed neuronal injury
• Diffuse brain swelling
• Diffuse ischemic injury
• Diffuse hypoxic injury
• Diffuse metabolic dysfunction
• Delayed neuronal injury
• Focal brain swelling
• Focal ischemic injury
• Focal hypoxic injury
• Regional metabolic dysfunction
For example, acute subdural hematoma (ASDH) is a good representative of focal brain injury which also has the aspect of both of primary and secondary brain injuries. In ASDH, neuropathologic study showed ischemic brain damage in the hemisphere underlying the hematoma . An important factor leading to this ischemic damage is raised intracranial pressure (ICP) producing impaired cerebral perfusion. Increasing ICP reduces the volume of cerebral blood circulation. Removal of the hemorrhage may result in the immediate reversal of global ischemia. And this abrupt reduction of mass lesion sometimes induces secondary “reperfusion injury” [14–16]. Previous experimental and clinical studies thus have shown that subdural hematoma and its removal was considered as an ischemic/reperfusion (I/R) pathophysiology in TBI [17, 18].
History and future direction of TTM for TBI
Historically, TTM were induced prior to surgery to assist procedures that caused prolonged ischemia, including open heart surgery [19, 20] and various organ transplants . Within its first decade, hypothermia was applied to multiple emergency situations that were characterized by ischemia such as stroke [22, 23], myocardial infarction , and cardiac arrest [25, 26].
Recent randomized clinical trials (RCTs) relating TTM on TBI
Age (years old)
No. of patients
Type of TBI
Time interval of temperature control
33 °C vs 37 °C
0.5 °C/2 h
57 % poor outcome in each group, NS
28 % TH vs 27 % Normo, NS
Clifton et al. 
Weak evidence of improved outcomes in patients who were initially hypothermic on admission
All, severe, 2.5 h after suffering TBI
33 °C vs 37 °C
0.5 °C/2 h
60 % TH 57 % Normo, NS
23 % TH vs 18 % Normo NS
Clifton et al. 
Early-induced hypothermia proved significantly efficacious for surgically evacuated hematoma
32-34 °C vs 35.5–37 °C
>72 h and
Relative risk (RR) 1.24, 95 % confidence interval (CI) 0.62–2.48, p = 0.597, NS
(RR 1.82, 95 % CI 0.82–4.03, p = 0.180) NS
Maekawa et al. 
Clinical Trial gov. NCT00134472 UMIN 000000231
Primary closed TBI with raised ICP >20 mmHg
32-35 °C vs Normo
48 h continued for as long as is necessary to reduce and maintain ICP <20 mmHg
Andrews et al. 
Longer TH (34–35 °C) for 5 days vs Normo (36–37 °C).
<0.5 °C/4 h
Lei et al. 
ClinicalTrials.gov Identifier: NCT01886222
ASDH with Evacuated (GCSM <6)
33 °C vs 37 °C Preoperative induction
ClinicalTrials.gov NCT02064959 and UMIN 000014863
The efficacy of early-induced therapeutic hypothermia was also proved in animal experimental TBI model. With considering the data of NABIS:H II, we also hypothesized that preoperatively early induced hypothermia maybe beneficial to mitigate reperfusional injury occurred by craniotomy and clot removal in ASDH rat model . Our data suggested that early, preoperatively induced hypothermia could mediate the reduction of neuronal and glial damage in the reperfusion phase of I/R TBI .
More recently, Maekawa et al. compared prolonged mild TH versus fever control with tight hemodynamic monitoring and slow rewarming in patients with severe traumatic brain injury with a multicenter RCT (B-HYPO) in patients with severe TBI  (Table 2). Patients were assigned to either therapeutic hypothermia (32–34 °C) or fever control (35.5–37 °C). Patients with therapeutic hypothermia were cooled as soon as possible for ≥72 h and rewarmed at a rate of <1 °C/day. There were no significant differences in the likelihood of poor neurological outcome or mortality between the two groups. However, one subanalysis of this study showed the efficacy of hypothermia especially for young TBI patients who had focal hematoma which needed evacuation .
Conclusively, large RCTs still have not yet shown the efficacy of TTM in TBI treatment (Table 2). However, subanalysis of RCTs and animal experimental research showed that early, preoperatively induced hypothermia may mediate the reduction of neuronal and glial damage in the reperfusion phase of focal brain injury which has I/R pathophysiology .
Now, an international multicenter RCT (HOPES Trial) is currently in progress. In this trial, nine Japanese centers and three centers in the USA are included as participants. The objective of this trial is to test whether hypothermia improves the outcome following TBI with ASDH requiring evacuation. The primary objective is to determine if rapid induction of hypothermia prior to emergent craniotomy for ASDH will improve the outcome as measured by Glasgow Outcome Scale-Extended (GOSE) at 6 months. Over 120 ASDH patients will be registered by 2018 (ClinicalTrials.gov NCT02064959 and UMIN 000014863).
The mechanisms of I/R brain injury and hypothermia treatment
Reperfusion to this ischemic tissue results in a short period of excessive free radical production . Experimental measurements of the reperfusion phase demonstrate that oxygen- and carbon-centered free radicals peak within 5 min of reperfusion  and that hydroxyl generation peaks within 15 min . This oxidative stress can damage proteins, lipids, and DNA, possibly leading to necrosis and apoptosis [47, 48]. Oxidants also modulate neuroinflammation  leading to increased levels of neuronal apoptosis in adjacent cells [50–52].
Despite much basic and clinical research using hypothermia in I/R brain injury, the mechanisms of its neuronal protection remain unclear. Most believe it to act through a multitude of different pathways. Mitochondrial free radical production might be an important target, and it provides a possible window of opportunity for hypothermia treatment. Supporting this point, hypothermia has been shown to decrease abnormal production of free radicals . Another potential mechanism of hypothermia involves reduction of the inflammatory cascade and cell death pathways of apoptosis and necrosis .
Hypothermia also reduces cellular metabolism and oxygen demand while maintaining acceptable ATP levels . Likewise, it improves cellular ion handling and cellular pH balance . In Fig. 1, we illustrate the schema of mechanisms of I/R injury and the estimated points where hypothermia treatment can effect.
How soon is the induction of TTM in order to be beneficial for brain injury?
The previous studies have shown that hypothermia must be achieved within 2 to 6 h of severe hypoxic-ischemic injury in animal models. For example, cooling sheep to 34 °C for 72 h gave good neuroprotection if started 90 min after the injury. It was partly effective if started at 5.5 h and was ineffective if started at 8.5 h . Most clinical trials have suggested that the earlier mild hypothermia is initiated, the more likely beneficial effects may be obtained . Hypothermia is currently being induced by surface cooling with use of cooling blankets, which usually requires 4 to 8 h to get the target hypothermia temperature (33 to 35 °C) [30, 57–59].
Bernard et al. reported that cooling can be achieved more rapidly (2 °C over 30 min) by intravenous administration of iced (4 °C) crystalloid solution .
Innovation of cooling device also enables rapid induction of TTM in TBI. Recently, the use of intravascular cooling device was spreading in the scene of neurocritical care. This device is now also approved in Japan and widely started to use for TTM in neurocritical care patients. Several reports that compare intravascular cooling to surface cooling exist. de Waard et al. compared the intravascular cooling device and surface cooling device and concluded that time to reach target temperature and cooling speeds was the same between two devices. And the variation coefficient for temperature during maintenance was higher in the surface than that for the intravascular cooling group (mean 0.85 % versus 0.35 %, p < 0.0001) . This use of cold intravenous fluids and new cooling devices may represent a logical strategy for future clinical trials for accurate TTM in severe TBI.
Therapeutic window for TTM
There are still no clear evidences on the optimal length of TTM in TBI. A recent experimental research showed that persisting lower temperature significantly reduced the synthesis of hypoxia-inducible factor 1 (HIF-1, a protein relating hypoxic tolerance) under hypoxic conditions and weaken adaptation to hypoxia . On the other hand, a clinical research showed the efficacy of longer hypothermia therapy for neuroprotection in TBI. Jiang et al. performed a single center randomized study to compare the effect of long-term (5 days) mild hypothermia versus short-term (2 days) mild hypothermia suggesting that mild hypothermia may improve the outcome in a series of 215 severe adult TBI patients, when cooling is maintained for longer than 48 h . More recently, a multicenter RCT to examine the efficacy and safety of long-term mild hypothermia (34–35 °C for 5 days) in severe TBI is planned in China (the LTH-1 trial) .
Rate of rewarming is also an important variable for influencing the protective effects of the hypothermia therapy. In the experimental setting, posttraumatic hypothermia followed by slow rewarming appears to provide maximal protection in terms of traumatically induced axonal damage, microvascular damage and dysfunction, and contusional expansion [63, 64]. In contrast, hypothermia followed by rapid rewarming not only reverses the protective effects associated with hypothermic intervention but also, in many cases, exacerbates the traumatically induced pathology and its functional consequences [64–66].
Conclusively, longer maintenance and slower rewarming may be beneficial in TBI. On the other hand, we also need to be cautious for severe side effects of longer hypothermia maintenance .
Preoperative-induced hypothermia for traumatic brain injury
Clinical studies using intraoperative hypothermia for neurosurgical procedures
Authors and year
No. of cases
Operative procedure (number)
Mean target temp (°C)
Mean duration of hypothermia (min)
Mean rewarming rate(°C/h)
Mean rewarming temp (°C)
Effectiveness of hypothermia
Baker et al.,  1994
30 (Normo 17, Hypo13 )
Elective craniotomy for supratentorial tumor resection (14), aneurysm repair (14), other (2)
Shivering (Normo 0 case vs Hypo 7 cases, p = 0.002). No severe comp.
34.3 ± 0.4
0.7 ± 0.6
35.8 ± 1.0
Clifton and Christensen,  1992
Aneurysm surgery with elective craniotomy (21)
Hindman et al,  1999
114 (Normo 57, Hypo 57)
SAH clipping (52), unruptured aneurysm clipping (62)
No significant difference between Normo and Hypo. No severe comp.
Sato and Yoshimoto  2000
60 (Normo 28, Hypo 32)
AC and WB
Time, 115 min (45–250 min)
Steinberg et al.,  2004
Elective open craniotomy for unruptured cerebral aneurysm
WB(61) vs endo(92)
Postoperative infection 4.3 % endo vs 4.9 % WB, NS. No severe comp. in all
1.88 (WB) vs 0.69 (endo)
NS between WB and endo
Todd et al,  2005
1000 (Normo 501, Hypo 499)
Postoperative bacteremia (5 % Hypo vs 3 % Normo, P = 0.05, no severe comp. in all.
324 ± 120
36.4 ± 1.0
Hindman et al.,  2010
441 (Normo 233, Hypo 208)
SAH patients undergoing temporary clipping
Time, 120 min
Induced normothermia and avoiding hyperthermia in TBI: is it effective?
Clinical studies that prove the efficacy of induced normothermia is much less than that of induced hypothermia. One study from Pittsburgh group showed the efficacy of induced normothermia (fever prophylaxis with intravascular cooling catheter) with reduction of intracranial hypertension compared to control group . More recently, Suehiro et al. reported the Japanese survey of brain temperature management (TH, intensive normothermia, and no temperature management) in patients with traumatic brain injury . In this survey, a total number of 1091 patients were analyzed. Favorable outcome was significantly higher with TH group (52.4 %) compared to intensive normothermia (26.9 %) and no temperature management (20.7 %). This data suggested that TTM is significantly effective for TBI management comparing to no temperature management.
Several other studies showed that hyperthermia was associated with a statistically significant increase in the increase of ICU stay, lower Glasgow coma scale score on discharge from ICU, and lower neurological function at 6 months after initial injury [80, 81].
Conclusively, appropriate thermoregulation with TTM (TH and intensive normothermia) is significantly important in TBI. Indeed, these data have led to several recommendations for and strict control of temperature in the neuro-ICU settings [82, 83].
TTM for controlling intracranial hypertension in TBI
Raised ICP and intracranial hypertension are important predictors of mortality in patients with severe TBI . Aggressive treatment of elevated ICP has been shown to reduce mortality and improve outcome [10, 85, 86]. TTM also has been a promising treatment strategy for controlling intracranial pressure in TBI [87, 88].
To clarify the effect of TTM for the treatment of intracranial hypertension, the latest clinical trial (EUROTHERM 3235) is now ongoing  (Table 2). In this trial, patient with refractory intracranial hypertension (ICP > 20 mmHg) is assigned as TH group or control group (standard treatment without any TTM). Two treatment groups are compared with mortality on the 28th day after injury or on discharge. The sample size of this study is estimated as 600 patients. Recently, preliminary data of this trial showed the efficacy of TTM with controlling intracranial hypertension . TTM may have a potential as a therapeutic option to control ICP in patients with severe TBI. The final result from this large RCT is waited.
In this review, first, we explained the classification of TBI pathophysiology. Then, we mentioned the possibility of mild therapeutic hypothermia with focusing on the treatment of I/R-related TBI and intracranial hypertension. With considering previous RCTs, now several multicenter clinical trials including HOPES, EUROTHERM3235, and LTH-1 trial are ongoing. Conclusively, TTM is still in the center of neuroprotective treatments in TBI. These therapies are expected to mitigate ischemic and reperfusional pathophysiology and to reduce intracranial pressure in TBI. Further results from these ongoing clinical RCTs are waited.
This work was supported by JSPS Grants-in-aid for Scientific Research Grant Number 26293386 and was supported in part by a research grant from the General Insurance Association of Japan.
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