Hypothermia Therapy

ANRV382-BE11-06
ARI
16 June 2009
ANNUAL
REVIEWS
Further
7:14
Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

by Kenneth Diller on 07/11/09. For personal use only.
Click here for quick links to

Annual Reviews content online,
including:
Other articles in this volume
Top cited articles
Top downloaded articles
Our comprehensive search
Hypothermia Therapy
for Brain Injury
Kenneth R. Diller1 and Liang Zhu2
1
Department of Biomedical Engineering, The University of Texas, Austin, Texas 78712;

email: kdiller@mail.utexas.edu
Department of Mechanical Engineering, The University of Maryland, Baltimore,

Maryland 21250
Annu. Rev. Biomed. Eng. 2009. 11:13562
Key Words
First published online as a Review in Advance on

April 13, 2009
hypothermia, neurological trauma, brain cooling, head injury, ischemia,

traumatic brain injury
The Annual Review of Biomedical Engineering is

online at bioeng.annualreviews.org
This articles doi:
10.1146/annurev-bioeng-061008-124908
c 2009 by Annual Reviews.
Copyright
All rights reserved
1523-9829/09/0815-0135$20.00
Abstract
Induced hypothermia is an acknowledged useful therapy for treating conditions that lead to cell and tissue damage caused by ischemia, including
traumatic brain injury, stroke, and cardiac arrest. An accumulating body of
clinical evidence, together with several decades of research, has documented
that the efcacy of hypothermia is dependent on achieving a reduced temperature in the target tissue before or soon following the ischemia-precipitating
event. The temperature must be lowered to within a rather small range of
values to effect therapeutic benet without introducing collateral problems.
Rewarming must be much slower than cooling. Many different methods and
devices have been used for cooling, with mixed results. There are existing
opportunities for bioengineers to improve our understanding of the mechanisms of hypothermia and to develop more effective methods of cooling the
brain following trauma.
135
ANRV382-BE11-06
ARI
16 June 2009
7:14
Contents

1. HISTORY OF HYPOTHERMIA TREATMENT IN MEDICINE . . . . . . . . . . . . . .

2. BIOLOGICAL AND CHEMICAL REACTIONS TO INJURY
IN THE HUMAN BRAIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. NEUROPROTECTIVE MECHANISMS ASSOCIATED
WITH BRAIN HYPOTHERMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. APPLICATIONS WITH IMPROVED CLINICAL OUTCOMES
BY BRAIN HYPOTHERMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Brain Ischemic Injury from Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Brain Ischemic Injury during Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. FACTORS AFFECTING THE PROTECTIVE OUTCOMES ASSOCIATED
WITH BRAIN HYPOTHERMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Time of Cooling Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Cooling Extent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Cooling Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Rewarming Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. CURRENTLY USED BRAIN HYPOTHERMIA APPROACHES . . . . . . . . . . . . . . .
6.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2. Whole-Body versus Selective Brain Cooling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3. Whole-Body Hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4. Selective Brain Cooling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. ENGINEERING CONTRIBUTIONS IN BRAIN HYPOTHERMIA . . . . . . . . . . .
7.1. Development of Cooling Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2. Mathematical Simulations of Cooling and Rewarming Processes . . . . . . . . . . . . . .
8. OPPORTUNITIES FOR BIOMEDICAL
ENGINEERING CONTRIBUTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
136
137
138
138
138
139
140
141
142
142
142
143
144
144
144
144
145
145
148
151
151
151
154
1. HISTORY OF HYPOTHERMIA TREATMENT IN MEDICINE
Hypothermia: state
in which the body core
temperature is reduced
at least 2 C below the
normothermia value
(37 C)
Ischemia: restriction
in blood supply, with
resultant damage to
the affected tissue
136
Cooling processes have been applied in medicine since ancient Greece. Over the intervening
millennia, developing an understanding of the function of the human thermoregulatory system
has been a subject of great interest, and eventually attempts were made to manipulate it for
therapeutic applications. During Nepoleons invasion of Russia, French surgeons noticed that the
soldiers left in snow had a better survival rate that those with a warm blanket. During and following
World War II, devices were developed for the explicit purpose of removing heat from the body
core via surface cooling garments that were worn by airplane pilots and astronauts. The availability
of cooling garments provided a method for inducing hypothermia (or avoiding hyperthermia) with
a greater level of control than afforded by more passive techniques such as whole-body immersion
into cold water or ice baths.
It is well documented that unconsciousness occurs within 15 s after complete occlusion of
cerebral arteries and that brain tissue cannot recover fully after only 5 min of normothermic brain
ischemia (1). Induced hypothermia has been studied as a means to protect the brain from ischemia
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
since the 1940s (210). Resuscitative cerebral hypothermia was introduced rst in cardiac arrest for
cerebral resuscitation in the 1950s (11). Later research focused on maximization of the ability of the
brain tissue to survive anoxic no-ow states as enhanced by hypothermia. In the 1960s and 1970s,
animal experiments and clinical studies showed the benets of hypothermia in prolonging the brain
time-tolerance to cardiac arrest. Hypothermia was also implemented in open-chest and open-heart
surgeries, including intracranial aneurysm clipping and arteriovenous malformation resection to
minimize injury to the heart and brain. Cardiopulmonary bypass was usually employed for patients
undergoing neurovascular surgical procedures, to allow for a bloodless eld for the surgeon and to
lesson the risk of hemorrhage. Bypass in conjunction with induced hypothermia provides cardiac
surgeons sufcient time for many procedures while avoiding permanent brain injury. The surgical
interruption time can be sustained for more than 45 min at 10 C versus less than 8 min at 32 C
(12). This application of hypothermia contributes signicantly to reduced mortality associated
with previously inoperable cardiac and cerebral pathology. Most of the neuroprotective effects
have been more evident in animal experiments than in patients.
Because early studies commonly used deep states of hypothermia 30 C, it is not surprising that many years of experimentation were required to identify the therapeutic bounds for
which hypothermia presents a clear efcacy. Research in hypothermia to enhance brain tissue
recovery after ischemic attack became dormant in the 1970s and the 1980s owing to thermal
management difculties and uncertainty of benets as well as detrimental systemic complications
associated with deep hypothermia. The idea of mild hypothermia has been re-investigated by
researchers since 1987 owing to encouraging animal experiments on canine, swine, and rodent
models. Because of the ability to better control the state of hypothermia in animals, extensive
experimentation on such models has been conducted to evaluate effects of cooling methods, temperature depression, hypothermia duration, cooling initiation relative to the ischemic event, and
rewarming rate on the brain recovery from ischemia. There is a large amount of experimental evidence of hypothermia-induced neuroprotection from ischemia injury in laboratory animals. The
neuroprotective mechanisms of hyperthermia have become increasingly better understood in the
past two decades. Supporting data in human subjects are still limited, especially for randomized
multicenter clinical trials (13). In clinical studies, hypothermia therapy seems more successful in
open-heart and neck surgery than in traumatic head injury. This is not unexpected, because initiating cooling before ischemia attack has been demonstrated to maximize the benets conferred
by hypothermia, although delay in initiation by 2 h or more has also shown limited benets in
both animal models and clinical studies. These foregoing studies in brain hypothermia have set
the stage for future investigations to develop more effective and well-controlled approaches for
treating brain ischemia. It is anticipated that hypothermia will be proven as an effective method
to limit and eliminate injury and death associated with brain ischemia, to the benet of a large
patient population.
2. BIOLOGICAL AND CHEMICAL REACTIONS TO INJURY

IN THE HUMAN BRAIN
Brain ischemia can be the result of ischemic stroke, cardiovascular and respiratory disorders, and
external physical trauma. If the initial damage is limited, the brain may be able to recover. If
the injury is extensive, secondary brain damage occurs, including intracranial hypertension (brain
swelling), hemorrhage, hypoxia, and edema. It is well known that brain oxygen stores become
exhausted within 15 s and brain energy stores become exhausted within 5 min after global ischemia
(1). Energy loss results in depolarization of cell membranes. A series of biochemical reactions and
cascades initiated by the trauma will then follow. Those cascade events evolve gradually and may last
www.annualreviews.org Hypothermia Therapy for Brain Injury
Hypoxia: deciency
of oxygen in tissues
137
ANRV382-BE11-06
ARI
16 June 2009
Reperfusion:
reestablishing of blood
ow in a vascular bed
following a period of
ischemia

TBI: traumatic brain

injury
7:14
several days after the initial trauma. Increase in extracellular K+ , energy depletion, disruption of the
blood-brain barrier, free radical release, excitotoxicity, and inammation are typical consequences
of those cascade events. Loss of selective neurons following global or local brain ischemia may
lead to permanent neurologic decit and even death.
3. NEUROPROTECTIVE MECHANISMS ASSOCIATED

WITH BRAIN HYPOTHERMIA
It has been suggested that hypothermia may modify a wide range of cell necrosis mechanisms.
Early studies have attributed the protective effects of hypothermia to reducing the energy expenditures of cerebral metabolic rates of glucose and oxygen. Brain oxygen consumption can decrease
by approximately 57% for every degree Celsius decrease in tissue temperature. However, the
improved outcomes associated with mild hypothermia suggest that it may play a role in deterring
deleterious biochemical actions following brain injury (1416). Hypothermia retards progression
of the ischemia cascade and pathologic neuroexcitation. The major mechanisms of neuroprotection by hypothermia are attenuation in the opening of the blood-brain barrier, reduction of
glutamate release, alleviation of inammation, and slowing of free radical generation and release.
It may impair glutamate-mediated calcium inux or directly inhibit calcium-mediated effects on
calcium/calmodulin kinase. As a result, hypothermia preserves high-energy phosphates that may
facilitate the maintenance of membrane integrity during ischemia, limit edema formation, lower
intracranial pressure, and interrupt necrosis and apoptosis (17). All of the mechanisms lead to long
neuronal survival and improve outcomes after reperfusion.
4. APPLICATIONS WITH IMPROVED CLINICAL OUTCOMES

BY BRAIN HYPOTHERMIA
4.1. Traumatic Brain Injury
Traumatic brain injury (TBI) is a nondegenerative, noncongenital insult to the brain tissue due to
externally inicted trauma (18). The major consequences of head injury include skull fractures,
intracranial hemorrhages, elevated intracranial pressure, and cerebral contusion. Unlike stroke,
which is often associated with senior citizens, TBI affects a predominantly young population.
Neuroprotective outcomes in clinical trials that treated head injury using hypothermia are not
consistent. There is marked heterogeneity among available clinical studies. In 1994, a multicenter,
randomized, prospective phase III study of systemic hypothermia in severe brain injury, involving
seven medical centers in the United States (13), was initiated based on the promise of decades of
somewhat sporadic experiments and anecdotal positive clinical outcomes for hypothermia used to
treat TBI in addition to an extensive phase II clinical trial (19). This study enrolled 392 patients,
ages 1665, who suffered coma from brain injury in the absence of other major traumas. A control
group received standard management with a nominal core temperature of 37 C. The treatment
group received the same management protocol at a target temperature of 33 C. There was a large
variation in the cooling induction time due to many individual circumstances. The cooling process
began at 4.1 1.2 h post injury via surface cooling technology, with completion by 8.3 3.0 h.
Hypothermia was maintained for 48 h, following which slow rewarming was distributed over
18 h. Some of the patients were already hypothermic (35 C) owing to independent circumstances
on admission to the hospital and were retained in a treatment subgroup. Overall, a very minimal
difference was observed between the treatment and control groups (13), with the exception of
the subgroup, already hypothermic at admission, which had signicantly better outcomes (20).
138
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
Although the results of this study were discouraging, they led directly to an enhanced appreciation
for the need to achieve a hypothermic state quickly following a TBI for the therapy to be effective
(21, 22). Thus, the stage was set for current developments in the application of hypothermia for
TBI.
Several clinical studies (2325) tested hypothermia therapy in patients with severe head injury
and achieved improved outcomes compared with normothermia groups. Hypothermia benets
were evident in patients with a coma score of 56 at months 3 and 6 (23). It is reported that more
than 62% of patients achieved good outcome in the hypothermia group versus 39% in the control
group. Jiang et al. (26) evaluated the long-term benets of hypothermia in patients with severe
traumatic head injury. It was found that mortality decreased by 40%, and the rate of favorable
outcome increased by 70% in the hypothermia group one year after the head injury. One of
the common benets identied in the above studies was a marked reduction of the intracranial
pressure in the hypothermia group after days of treatment. It was recommended that cooling
should be maintained at least until after the intracranial pressure returns to the normal range (25,
26). Some researchers (27) attributed the failure of demonstration of benets by hypothermia to
the delay of cooling initiation, which is often more than 4 h after the injury in clinical treatments
(13). A more recent paper (28), which showed that more than 87% of patients have achieved good
neurological outcome in the hypothermia group, suggested certain methodological discrepancies
in the Clifton study. The latest clinical trial of hypothermia on traumatic head injury (29) showed
improved extradural pressure and reduced mortality from 51% in the control group (43 patients)
to 26% in the hypothermia group (also 43 patients). Another clinical study by the same group
(30) documented improved neurological outcome in TBI patients two years after the hypothermia
treatment, with complications that were manageable. A recent review by Peterson et al. (31) of
hypothermia-related neuroprotection on TBI patients identies a cooling duration longer than
48 h as a favorable factor; however, it cautions the risk of pneumonia. Based on the review, the
strong evidence of the long-term (more than one year) benets of hypothermia suggests following
up with patients for one to two years in future hypothermia studies for TBI patients (31). Overall,
there is a lack of well-controlled, large clinical trials that provide convincing evidence of the
benets and safety of brain hypothermia for traumatic head injury patients. In the third edition
of the Guidelines for the Management of Severe Traumatic Brain Injury, issued by the Brain
Trauma Foundation in 2007, it is stated that mild hypothermia should be exercised with caution
for patients with TBI (32).
4.2. Brain Ischemic Injury from Stroke

The 2005 Guidelines on Acute Stroke Treatment by the American Stroke Association identify
hypothermia after stroke as a promising eld of research. A recent review by van der Worp
et al. (33) concludes that hypothermia improved outcomes of animals suffering from ischemic
stroke by more than 30%. This result is especially true in well-controlled animal stroke models
(34). It is relatively easier to have reproducible models of transient global brain ischemia via
occlusion of the distal middle cerebral and ipsilateral common carotid arteries than of focal brain
ischemia, for which it is more difcult to dene experimental conditions. Computerized images of
cerebral infarct volume and edema are commonly used to evaluate ischemic damage to the brain
tissue. If the animals are kept alive after the injury, cognitive evaluation is conducted to assess
the long-term protective outcome of cooling. The efcacy of hypothermia is better with lower
target temperature (35) and/or when initiated before or during the onset of ischemia. A study
by Kurasako et al. (36) on a spontaneously hypertensive rat model demonstrated a strong, linear
temperature-dependent reduction in infarct volume and edema progression in transient focal
139
ARI
16 June 2009
7:14
ischemia. Neuroprotection by hypothermia is more prominent in lower-temperature (28 C and

30 C) groups. More improvements are found in temporary than in permanent ischemic models
(35, 37).
There are limited clinical trials to test the efcacy and safety of various hypothermia approaches
for acute ischemic stroke patients. Clinical studies by Schwab et al. (3840) showed that more
than half of the patients survived severe stroke after up to 72 h of moderate hypothermia at 33 C.
Most of the 38% mortality rate of the stroke patients occurred during the rewarming process,
which suggests the important role played by gradual rewarming after hypothermia. Although the
clinical studies were not conducted using a control group, the observed 38% mortality rate is
much lower than a typical death rate of 70% in severe stroke patients (41, 42). A small clinical
trial by Kammersgaard et al. (43) that used mild hypothermia (35 C) in 17 patients also showed
marked improvement of mortality rate, from 23% in controls to 12%. Unlike the Schwab studies
associated with many serious systemic complications, including thrombocytopenia, bradycardia,
and pneumonia, the only reported side effect in the Kammersgaard trial was shivering, which was
treated by pethidine. Kasner et al. (44) conducted a clinical trial with mild hypothermia induced
by acetaminophen administration in an attempt to achieve brain cooling rapidly. The results were
inconclusive because acetaminophen produced only a very mild state of hypothermia, <36.5 C,
bringing question to its clinical efcacy. A randomized trial of hypothermia in infants with hypoxicischemic encephalopathy showed reduced risk of death or disability (45); however, neuroprotection
from hypothermia was not obvious in another two clinical studies (46, 47), although the results
favored hypothermia.

ANRV382-BE11-06
4.3. Brain Ischemic Injury during Surgery

Cardiopulmonary bypassrelated brain injury is a common postsurgical observation. A multicenter study by Roach et al. (48) demonstrated that more than 6% of patients suffered adverse
neurological outcomes after coronary artery bypass grafting. Neuropsychological decits (cognitive changes) were reported in more than 20% of patients eight weeks after bypass surgery (49).
It is believed that neurological dysfunction results from regional or global brain ischemia as a
consequence of hypoperfusion. Early experimental studies on animals suggested that brain tissue
remained partially ischemic after resuscitation from circulatory arrest, and delayed ischemia was
observed during the following hours. In both intracardiac and extracardiac surgeries, formation
of emboli is the major factor contributing to most neurological complications (50). Animal and
clinical studies showed that some patients developed severe neurological decits after surgeries involving unilateral common carotid occlusion (51). The decits were attributed to lack of posterior
communicating arteries following carotid occlusion.
The main effects of brain hypothermia include decrease in intracranial pressures and cerebral
edema, reduction of tissue oxygen demands, and amelioration of numerous deleterious cellular
biochemical mechanisms, including calcium shift, excitotoxicity, lipid peroxidation and other free
radical reactions, DNA damage, and inammation (52). Hypothermia during experimental cerebral ischemia provides potent, dose-related and long-lasting neuroprotection (53, 54). Conversely,
an elevated brain temperature of only 12 C strikingly worsens experimental neuronal injury and
clinical outcome (55). Experimental studies have shown that brain hypothermia enhances the
brains tolerance to ischemia and thereby improves neurological outcomes. Therapeutic mild hypothermia was implemented as a standard therapy in the international resuscitation guidelines.
Several animal studies (5658) have been performed to assess neuro-decit score in dogs after
bypass surgery. Profound brain hypothermia improved signicantly the neuro-decit score of the
control group (48.3) to 19.2 in the cooling group (0 = normal and 100 = brain dead). Improved
140
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
neurological outcome was shown in a dog model of cardiac arrest (59). In a study by Moyer et al.
(60), spontaneous cerebral hypothermia of 33 C decreased focal infarction volume in a rat brain by
75%. Mild brain hypothermia was reported to minimize cerebral impairment in 1500 patients undergoing pulmonary endarterectomy (61). The protective effect of hypothermia was also evident
in patients undergoing carotid endarterectomy (62), wherein there were no early postoperative
strokes or reversible ischemic neurological decits following the surgery. Two randomized clinical
trials in large groups of patients with global cerebral ischemia after cardiac arrest reported that
the number of patients with good outcome increased at least 40% in the hypothermic group, although the mortality rate was similar in both groups (63, 64). Recently, an FDA-approved cooling
system (ChillerPadTM and ChillerStripTM System, Seacoast Technologies, Inc., Portsmouth, NH)
was employed in a clinical trial of aneurysm repair, and hypothermia markedly reduced vasogenic
edema and protected the blood-brain barrier (65). However, this technology only supercially
cools the surface of the skull and does not provide deep brain cooling.
4.4. Multiple Sclerosis

Multiple sclerosis (MS) is a neurological disease associated with the destruction or loss of myelin
surrounding nerves. The major symptoms experienced by MS patients include spasticity, fatigue,
dizziness, loss of visual acuity, tremor, pain, and cognitive disability. The symptoms tend to get
worse when the body temperature is even slightly elevated. Early experiments using in vitro
preparations of demyelinated nerves (66, 67) demonstrated that a small increase in temperature
shortened the duration of the action potential, and the available current was insufcient to excite
the ranvier node connecting myeline sheath cells. Since demyelination may lead to conduction
block, disuse, and nally cell death, an increase in neuronal activity by decreasing nerve temperature can, in theory, prolong the action potential duration and induce sufcient current to
depolarize the ranvier node. Studies have shown that the restored neuronal activities may lead
to proliferation, migration, and maturation of myelin-producing cells (68, 69). Therefore, cooling has the potential to slow the progression of multiple sclerosis by fostering remyelination and
protecting the axon from degeneration.
There are several types of body cooling garments, based on heat removal from the surface
via evaporation, ice pack, or refrigeration, that are available to this patient population. Most MS
patients using a lightweight cooling vest found that the symptoms were alleviated (70). A cold
bath or swimming also provides better management of heat-related symptoms. In a controlled
experiment, improvements in acuity, timed walk and muscle strength, and reduction in cytokine
production were demonstrated in a cooling group when compared with controls (71). Localized cooling on the wrist and forearm while keeping the heart rate and body core temperature
unchanged illustrated a clear reduction of overall tremor amplitude and frequency during a steptracking task in MS patients (72). Aerobic exercise is usually recommended to mild-to-modest MS
patients because it provides tness and psychological benets similar to those in a healthy subject,
including increased strength and endurance, reduced depression, increased positive moods, and
improved cardiovascular tness (7378). However, exercise will lead to a rapid increase in body
temperature, which compromises the patients ability to function. The detrimental effects of body
temperature increase can be offset by cooling before or during exercise. A new device that enables
highly effective heat removal from the body core reduces exercise-related heat stress and thereby
increases the physical performance capacity of heat-sensitive individuals with MS (79). As a consequence, cooling may help MS patients gain greater independence and may improve their quality
of life.
141
ANRV382-BE11-06
ARI
16 June 2009
7:14
4.5. Heat Stroke

Heat exhaustion and heat stroke are the most common heat-related diseases involving dysfunction
and/or failure of temperature control in the human body. They usually occur when the body is subjected to elevated ambient temperature and during strenuous exercise. When body hyperthermia
lasts for a prolonged period of time, neurological abnormalities such as hallucinations, seizures,
and coma can occur, with the further effects of organ failure, permanent brain damage, and death.
More than 300 heat strokerelated deaths are reported in the United States annually. Heat stroke
resulted in more than 14,000 deaths in France during the 2003 summer heat wave (80).
The primary treatments of heat stroke include immediate cooling and support of organ-system
dysfunction (81). There are several approaches for rapidly cooling the body after the onset of heat
stroke. The rst steps are always moving the patient to a cool place away from environmental heat
sources and removing excess clothing. Internal cooling approaches include water irrigation lavage
or an intravascular catheter. External cooling can be produced with convection or conduction
sources applied to the skin surface. Internal methods are obviously more invasive than external
methods, are usually associated with collateral risks, and may cause water intoxication in patients
with compromised health. Some external methods aim to promote evaporative cooling on the skin
surface via spraying tepid water and/or using fans to increase air circulation (8286). Unfortunately, these methods tend to be counterproductive because they promote vasoconstriction, which
increases the thermal resistance between the body core and the skin surface, where heat can be
rejected to the environment. The median time for evaporative cooling to achieve a target rectal
temperature of 38 C varies widely with the presenting state of hyperthermia and is often well over
an hour. This method has limited efcacy if the humidity of the surrounding environment is near
saturation. Other external cooling techniques are accomplished by increasing the temperature
gradient through the tissue. Practical approaches include immersion in cold water (82, 87, 88)
and surface application of a cooling blanket (87, 89) or ice packs (90). Immersing patients in iced
water is messy and poorly tolerated, and it does not allow attachment of some types of monitoring equipment. The challenge in implementing the conduction method is to prevent the skin
temperature from falling below 30 C to trigger shivering. Numerous studies have demonstrated
the detrimental effects of vasoconstriction and shivering on patients. Vasoconstriction results in
decreased cutaneous blood perfusion, which impedes convective heat transfer from the body core
to the skin and therefore, compromises the bodys ability to lose heat fast. The application of
cooling to the surface of glabrous skin in which the arteriovenous anastomoses are distended and
owing enables blood circulation to the body core to provide an effective convective pathway for
rejection of core heat in thermally stressed indiciduals (91).
5. FACTORS AFFECTING THE PROTECTIVE OUTCOMES

ASSOCIATED WITH BRAIN HYPOTHERMIA
5.1. Time of Cooling Initiation
Numerous controlled animal experiments have demonstrated the benet of initiation of cooling
before the brain injury to confer signicant neuroprotective outcomes. Of course, precooling is an
option only for circumstances under which the onset of brain ischemia is foreseen. Precooling is a
clinical option for open-heart and neck surgery. Experimental data from a rat model demonstrated
the greatest benets of neuroprotection when hypothermia was induced during global ischemia
(92). Initiation of hypothermia before the injury completely prevented secondary brain damage
in gerbils (93).
142
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
For all the other clinical applications involving human subjects, precooling is not usually possible. The general consensus is to initiate brain hypothermia as early as possible following an
ischemia-precipitating event, although some studies have shown neuroprotective effects even
when the treatment was delayed by up to 6 h (94). Brain injury mechanisms typically progress
rapidly within 36 h after the initial injury. Hypothermia can reduce the initial inammatory response after head trauma so as to minimize or prevent secondary brain injury. It is well accepted
that there is a 12 h treatment window for animal models, after which the benets of hypothermia
are strongly diminished. However, it is difcult to correlate rodent data directly to humans. On the
basis of the present data, it may be concluded that the treatment window is probably very brief for
postischemic hypothermia to be effective in humans. A randomized and controlled experimental
study in a rat model by Markgraf et al. (95) showed signicant reduction of neurological decits
if the cooling is initiated within 60 min rather than 90 min after the injury. A recent clinical study
(96) demonstrated a reduction of hypoxic brain injury and improvement of neurological outcome
after cardiac arrest if mild hypothermia is initiated within the 90 min treatment window. However, experimental data also imply that delayed cooling can provide neuroprotection if the cooling
period is long with gradual rewarming (97, 98).
The inconsistency in patient outcome in various clinical studies, particularly involving head
trauma, might be due to the delay of hypothermia initiation and possible other uncontrolled
factors. A paper by Clifton et al. (13) has been cited widely in the hypothermia community as
evidence of ineffectiveness of hypothermia therapy for head trauma. However, as pointed out
by Safar & Kochanek (27), the negative results for clinical trials on head-injured patients may
be due to the delay in initiating cooling for up to 8 h after the injury in most patients studied.
Clifton subsequently noted that the apparent window of opportunity for gaining the benet of
hypothermia extends to only 90 min post trauma (21), and he is currently conducting a large
clinical trial to measure the effect. It is still a challenge to shorten the time between the injury
and induction of hypothermia. Usually, the process of transporting the patients to the hospital
is unproductive for this objective. A portable sensor attached to the patient to alert the medical
center of the impending case can minimize delay of treatment. Further, simple cooling approaches
that can be implemented by the Emergency Medical Service (EMS) personnel in the ambulance
have been suggested.
5.2. Cooling Extent

Because tissue temperature has profound effects on local metabolism and cellular activities, it
is expected that different depths of hypothermia have varying effects on the clinical outcome of
minimizing secondary brain injury. Brain hypothermia can be categorized as deep/severe (<28 C),
moderate (2832 C), and mild (3235 C) (99). The traditional view that colder is better (100)
has been questioned in the past decade (101). As brain temperature is decreased, greater systemic
toxicity is observed, and the adverse effects outweigh the neuroprotection mechanisms associated with therapeutic hypothermia (102). Deep hypothermia is associated with arrhythmias (103),
cardiac complications (104), coagulopathies (105), and pulmonary infections (106). In addition,
severe or moderate cooling usually requires sedation and mechanical ventilation. Therefore, deep
cooling approaches are limited to facilities that have intensive care units and that medically justify
the collateral complications. Many animal studies suggest that the preferred cooling temperature for neuroprotection is between 32 and 35 C (94, 107). Many studies have shown improved
neurological outcome using mild hypothermia, compared with either the deep cooling group or
the normothermia group. Typically, these studies use whole-body cooling. One may conjecture
whether the associated systemic complications of hypothermia can be avoided if only the brain
143
ANRV382-BE11-06
ARI
16 June 2009
7:14
tissue is cooled and the rest of the body kept normothermic. In addition, when whole-body cooling
is implemented, the brain can be assumed to be isothermal due to its high blood-perfusion rate.
Under these circumstances, there is minimal differential between the body core temperature and
the brain temperature, but large temperature variations may be created within the brain tissue if
cooling is applied to the head surface. Temperature gradients in the brain make control of the
hypothermia state in a target tissue region a difcult task. More studies are needed to understand
the tolerance of brain tissue to local cooling.
5.3. Cooling Duration

Secondary effects of brain injury, including edema and elevated pressure, are known to persist
several days after focal cerebral ischemia (108). Therefore, prolonging brain hypothermia therapy for an equivalent period may benet those patients. Cooling for less than 1 h provided no
neuroprotection in a rat model (92). Short periods of cooling may lead to transient rather than
permanent neuroprotection. Experimental studies have tested whether a long cooling duration is
safe for patients. Initially, 24 h were proposed, and later, the cooling duration was extended by
Bernard & Rosalion (134), Clifton et al. (19), McIntyre et al. (18), and Shiozaki et al. (25) to 48 h.
A recent review by Peterson et al. (31) documents profound neuroprotective benets observed in
patients with more than 48 h of hypothermia. Iwata et al. (109) note that the cooling extent and
cooling duration may not be two independent factors in determining patient outcomes.
Although prolonged cooling may maximize clinical neurological benets, it may also increase
systemic complications associated with cooling, especially in patients having compromised health.
The optimal duration of treatment remains unknown for clinical application, especially when
other confounding factors are involved. Closely monitoring patients during hypothermia therapy
should be an important planning consideration.
5.4. Rewarming Rate

The importance of controlling the rewarming rate in the brain tissue from a state of hypothermia
has been widely documented. Rapid rewarming may result in a dangerous rebound of intracranial
pressure elevation and cerebral perfusion pressure reduction; the importance of gradual rewarming has been emphasized in multiple clinical studies (25). Previous theoretical analysis (110) of
simulated passive (and uncontrolled) rewarming by removing the cooling device yields an average
calculated rate of approximately 3 C h1 . Recent animal experiments on rats (111) suggest that the
fast rewarming rate might result in a mismatch between the local blood perfusion and metabolism.
As suggested by Thoresen & Wyatt (112), the rewarming rate in tissue should be conducted slowly
at 0.5 C h1 . In some clinical trials, rewarming from hypothermia is conducted with a feedback
control system over 18 h. It is critical to develop a thermoregulating system that allows not only
fast cooling but also an adjustable rewarming rate.
6. CURRENTLY USED BRAIN HYPOTHERMIA APPROACHES

6.1. Overview
The ability to cool deeply embedded interior tissue such as the brain is limited by considerations of
the second law of thermodynamics. Unlike the heating process, which can be dissipative, cooling
requires that a negative temperature gradient be applied across the interstitial transport medium.
If conduction is used to effect the heat transfer process, the magnitude of cooling that can be
produced is directly proportional to the gradient that can be established across the medium and
144
Diller
Zhu
ANRV382-BE11-06
ARI
16 June 2009
7:14
the thermal conductivity of the medium. Alternatively, convective blood ow can be used as the
primary mechanism to remove heat from the body core and redistribute it to the surface area.
This mechanism is dependent on the level of blood perfusion through the cutaneous circulation
in conjunction with conduction through the skin and cooling on the surface. A different option
for cooling by convection is to introduce a chilled perfusate solution directly into the circulatory
system, although this approach is highly invasive and has inherent risks. Both approaches have
been adopted for inducing brain hypothermia, although heat removal by conduction through the
overlying tissue, including the skull, is of limited efcacy owing to the poor thermal conductivity
of bone.

6.2. Whole-Body versus Selective Brain Cooling

Most of the clinical studies to date have examined only systemic (whole-body) hypothermia. Either
the whole body mass or the cardiac output is cooled using this approach. The major methodological
drawback of this approach is the inherently slow cooling rate (0.5 h1 ) due to the large volume
of the human body to be cooled and the increase in thermal resistance due to arteriovenous shunt
vasoconstriction (23, 39, 47). When extracorporeal blood cooling is applied, the cooling rate can
be greatly improved; however, the procedures are highly invasive and require extensive supporting
equipment. With either approach, the major concern relating to whole-body cooling is that it may
produce deleterious systemic effects such as metabolic, cardiovascular, pulmonary, coagulation, and
immunologic complications (23, 113). The increased risk of systemic complications when using
whole-body hypothermia may outweigh the neuroprotective benets of such therapy. Further,
because of the long characteristic time of the human body, whole-body hypothermia may easily
miss the treatment window when hypothermic protection of the brain can be maximized.
Cooling the entire body to achieve a temperature reduction in the brain may not be necessary
because the human brain represents only 2% of body mass, and it receives 20% of resting cardiac
output. Thus, blood circulating to the brain could be an effective transport medium if there
were a method by which it could be cooled. Accordingly, in recent years, selective brain cooling
(SBC), in which the brain temperature is reduced while the rest of the body is kept normothermic,
has been proposed. A selective brain cooling technique would minimize serious adverse systemic
complications (114) and maximize the protective benets of hypothermia if it is initiated before
or during the ischemic event. In this approach, the brain tissue is cooled directly or the blood
supplied to the brain is cooled. The small mass of the head makes the cooling relatively fast
compared with whole-body cooling. The common carotid and vertebrate arteries are the major
blood vessels supplying blood to the brain and are somewhat accessible to cooling from the
overlying skin surface. Arterial blood temperature can be reduced via intravascular cooling, for
which commercial devices are available, or through skin surface cooling, if an imposed temperature
gradient can adequately penetrate the tissue and reach the blood vessels. Conducting heat from
the brain through the skull results in an unacceptably long process for inducing hypothermia.
6.3. Whole-Body Hypothermia

6.3.1. Skin surface cooling. Skin surface cooling is the most studied method in hypothermia.
This approach can promote heat transfer by evaporation from the skin and by imposing a temperature gradient from the body core to the skin. Various methods have been used to cool the skin,
including convective air circulation, cooling blankets/jackets, water mattresses, ice packs, and alcohol or ice water bathing. Surface cooling is an easy approach and does not require sophisticated
equipment. A clinical study by Mayer et al. (115) compared two surface cooling systems (Subzero
145
ARI
16 June 2009
7:14
and Arctic Sun) in controlling fever in neuro-critical-care patients and found positive outcomes
in reducing fever burden in both systems. Arctic Suntreated patients spent less time febrile, and
the cooling rate to achieve normothermia was faster than in the Subzero group. The side effects
included shivering, which occurred more often in the Arctic Sun group. To control shivering,
another clinical study gave a stroke patient pethidine while implementing a cooling blanket with
a ow of cool air at 10 C (43). Hypothermia reduced mortality at 6 months after stroke by 50%
from the control group. However, neurological impairment was only slightly improved and was
not signicantly different from the controls. Inducing mild whole-body hypothermia for 34 h in
head trauma patients with a coma score of 57 greatly improved the patients outcome (62% in the
hypothermia group versus 38% in the control group) in a randomized, controlled clinical trial on
87 severe head injury patients (23). A pilot study by Eicher et al. (116) on moderate whole-body
hypothermia (33 C) versus normothermia in excephalopathic neonates demonstrated favorable
neurological outcomes.
In addition to introducing vasoconstriction and shivering, there are other drawbacks. Full
body immersion makes it difcult to attach monitoring sensors to patients, and fast reduction
of temperature is prevented by large body mass, thus elongating the time it takes to achieve the
target temperature (117). Also, vasoconstriction induced by skin surface cooling greatly increases
the thermal resistance of the skin, further hindering heat transfer from the body core to the
surface. It is reported that 3.511 h are needed to reach 33 C using a cooling blanket (118). In
the Copenhagen Stroke Study (43), it took more than 5 h to decrease the body temperature by
2 C; however, surface cooling may be more appropriate for children because they inherently have
a smaller thermal mass than adults. Less than 1.5 h were required to achieve a body temperature
of 33.5 C in newborn infants using a blanket precooled to 5 C (45).

ANRV382-BE11-06
6.3.2. Blood cooling

6.3.2.1. Intravascular cooling catheter. Veno-venous extracorporeal blood cooling was proposed
as a method to induce a fast cooling rate (119125). This is a very attractive technique because it
bypasses the thermal resistance of tissue and connects directly to the cardiac output. This method
uses a covered cooling catheter that is inserted into the femoral vein and advanced to the inferior
vena cava via abdominal X-ray guidance. The catheter is coated with antithrombotic coverings
to prevent clotting. Coolant is pumped to the catheter to achieve a fast heat removal from the
venous blood, with a cooling capacity of up to 150 W. In well-controlled studies using large and
small animal models, the targeted brain temperature of 33 C was reached within a reasonable
time frame after cooling initiation. The reported clinical trials have shown cooling rates varying
between 0.9 and 6.9 C h1 , with hypothermia well tolerated by the patients. Some of the typical
complications associated with body surface cooling, such as infections, coagulopathy, and cerebral
edema, were not observed in animal experiments using the cooling catheter (125). In addition,
by keeping the skin warm, shivering did not occur, because shivering is, in part, driven through
skin receptors. However, the surgical procedure involved is invasive, and vessel access time varies
greatly with the skill of the surgeon. Therefore, its clinical use has been limited to special hospitals,
and it is not a technology available to personnel with limited training and resources (122).
There is no dispute that the cooling catheter is capable of reaching a targeted brain hypothermia
state within a short time owing to its powerful cooling capacity (126128). In well-controlled
animal experiments, the neuroprotective effects induced by the cooling catheter were all positive.
One clinical study (46) showed slight decrease in lesion size measured by diffusion weighted
imaging (DWI); however, the decrease was not signicantly different from that in the control
group. Conicting reports concerning the effect on brain function suggest that other uncontrolled
146
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
factors may play a role. For example, in most clinical studies, the cooling was usually not initiated
until several hours following the injury. The delays in cooling may diminish or even abrogate
the benecial effects of hypothermia. This approach was also implemented to reduce the size
of myocardial infarct in a pig model weighing from 60 to 80 kg (119, 129). Only 9% of the left
ventricular myocardial area is at risk of infarct with hypothermia compared with the normothermia
group (45%). Similar to other clinical trials for cardiac arrest, a recent clinical trial (126) found
short-term favorable neuroprotection in the hypothermia group using an endovascular cooling
approach. A fast cooling rate (1.2 C h1 ), long cooling duration (24 h), and gradual and wellcontrolled rewarming rate (0.5 C h1 ) may be contributing factors that improved the survival
rate with favorable neurological outcomes and reduced patient mortality (127). Additional wellcontrolled and randomized clinical studies are still needed to demonstrate the safety and long-term
efcacy of endovascular cooling.
6.3.2.2. Intravenous flushing. Chilled normal saline has been suggested as a preferred resuscitation uid for patients with neurological and neurosurgical injuries. It is inexpensive, easy to
store, and frequently utilized as hydration uid in hospitalized patients. This method of inducing hypothermia was tested in a swine model (129). For an extremely high intravenous infusion
rate of 120 ml min1 , a core cooling rate was measured at up to 18 C h1 . In a clinical study
(130), ringers solution was infused at a rate of 100 ml min1 to patients after resuscitation from
nontraumatic cardiac arrest, and no serious adverse hemodynamic complications occurred. This
approach is certainly very effective in achieving fast cooling. However, it is questionable whether
the patients can tolerate such a large infusion rate. A theoretical analysis (131) was performed
recently to simulate the reduction of body temperature using this approach. Unlike the animal
study during which the ow rate was very high, the simulation focused on a realistic and safe upper
limit of the infusion rate of either cold saline or 50% ice slurry saline mixture. The model identied a cooling rate of 0.48 and 0.24 C h1 using 50% ice slurry and chilled saline, respectively, at
450 ml h1 .
The use of cooled peripheral infusion is safe and likely without signicant side effects if the
patients can tolerate the additional uid. Inducing mild hypothermia in awake stroke patients
using cooled intravenous uid seems unlikely to cause discomfort. 30 ml kg1 of Ringers solution
was infused at a rate of 100 ml min1 into the antecubital vein in a clinical study by Badjatia et al.
(132), which was successful in controlling fever in patients within 2 h. Within approximately
3 h, it was possible to cool the body temperature from 36 to 34 C using two liters of cold
saline at 4 C (133). The observed cooling rate is similar to that predicted by the theoretical
model (131). In a recent case report by Bernard & Rosalion (134), a large volume of chilled
saline at 4 C was injected intravenously during cardiopulmonary resuscitation, and the patient
made a satisfactory recovery. Lopez et al. (135) infused four to six liters of 3 C lactate ringer at
0.1 ml kg1 min1 into healthy, awake volunteers to demonstrate the lack of side effects.
Shivering, which was observed in controls between 35.6 and 36.8 C, was avoided, as the subjects
skin temperature was maintained above 36.7 C (135). Infusing healthy, awake volunteers with 4 C
intravenous uids at 40 ml kg1 h1 , Frank et al. (136) demonstrated that the rst signs of thermal
discomfort occurred only when the body temperature reached 36 C. Because of a lower shivering
threshold, elderly may be susceptible to infusions of coolants when compared with the younger
population. No cardiac abnormalities were observed during or after the cold uid infusions (137).
Based on mathematical modeling, peripheral infusions of saline in chilled or ice slurry form can be
used as an adjuvant therapy to achieve mild hypothermia or to control fever. Intravenous coolants
administered in an on-demand, temperature-guided, and supervised setting seem a reasonable
147
ANRV382-BE11-06
ARI
16 June 2009
7:14
approach for core cooling to avoid potentially unsafe use of extended uid volumes and infusion
time periods.
6.4. Selective Brain Cooling

6.4.1. Head surface cooling. Head surface cooling via a helmet or an ice pack is practicable and
easy to apply, even in the prehospital setting. Saline perfusion to the subdural space has also been
suggested to cool the brain (138). Previous studies have indicated that it takes less than 1 h to
establish a steady-state temperature eld after head surface cooling. This gives EMT personnel
an advantage when cooling is initiated in the eld to maximize neuroprotection of hypothermia
treatment. One clinical study evaluated the performance of a cooling helmet based on a NASA
spin-off technology (114). In the hypothermia group of eight enrolled patients, brain temperature
dropped more than 1.8 C within 1 h of the helmet application. Systemic cooling occurred only
after a prolonged cooling of more than 6 h. Minimal systemic complication was observed using the
helmet cooling. The clinical study (114) demonstrated that head surface cooling using a helmet
is a relatively effective way to induce and maintain brain hypothermia while keeping the rest of
body at normothermia.
An ice pack can more efciently cool the brain tissue than a cooling helmet with the same coolant
temperature of 0 C. Recent theoretical modeling showed the effects of a large thermal resistance
between the coolant and scalp. Experiments on MS patients (139) and theoretical simulations (110)
showed that the head skin temperature is approximately 20 C using a cooling helmet with 0 C
coolant circulating inside. Improving the thermal contact between the coolant and scalp would, in
theory, shorten the time required to achieve targeted cerebral hypothermia and improve cooling
penetration to the deep brain tissue. In the experiment performed in a cat model, 20 C cold saline
was induced to the subdural space of the cerebral hemisphere by a catheter inserted into a parietal
burr hole (138). The temperature was well tolerated by the subjects and effective in lowering
the brain temperature. It showed that hypothermia has enhanced the recovery of somatosensory
evoked potential in the animal model after 1 h of transient middle cerebral artery occlusion (138).
A similar design of a cooling chamber was used to induce brain hypothermia by placing it on the
cerebral cortex of the anterolateral temporal lobe of 18 patients (140). Chilled saline was infused to
the chamber. Temperatures lower than 25 C were established in the cortex 6 mm below the surface
of the cooling chamber. The changes in spontaneous and stimulus-evoked electroencephalogram
(EEG) activity were due to local cooling. This approach is considered safe because no adverse
effects were observed, although more rigorous clinical study is needed to evaluate the risks and
benets of this hypothermia technique on patient neurological outcomes.
Head surface cooling relies on heat conduction from the scalp to the inner region of the brain
hemisphere. Thus, because of the imposed radial temperature gradient, head surface cooling
provides more preferential cooling of the supercial areas of the brain than the deep regions. This
method of hypothermia induction can involve an interplay of conduction and convection effects.
Large temperature gradients occur in the brain tissue, and temperature variation depends strongly
on the local blood perfusion rate. A temperature variation of more than 7 C across the brain has
been reported (141). Theoretical simulations of temperature elds of head structures during head
surface cooling demonstrated similar trends as observed in the animal experiments. Cooling from
the head surface has to overcome the thermal barrier of the scalp and skull as well as the large
blood perfusion rate in the brain tissue (110, 142). Signicant cooling of the white matter is not
feasible unless the brain tissue is ischemic.
The benecial effects of selective brain cooling using a cooling helmet are more evident in
infants owing to their smaller head size. A cooling cap lled with 30 C solution was introduced
148
Diller
Zhu
ANRV382-BE11-06
ARI
16 June 2009
7:14

to infant piglets after cardiac arrest and resuscitation (143). Brain temperature was reduced from
37 C to 31 C within 1 h. Although the temperature of the coolant in the cap was below 0 C, no
necrosis was observed. This implies that there was no freezing damage to the skin surface owing to
the thermal barrier of the cap material and the air gap between the cap and the skin. A recent clinical
trial on infants with moderate to severe neonatal encephalopathy demonstrated favorable neurodevelopmental outcomes in infants with less severe amplitude-integrated electroencephalogram
(aEEG) changes after 72 h of selective head cooling using a cooling cap (144). Experimental
measurements of brain temperatures on newborn swine showed temperature reductions at all
brain sites (141).
6.4.2. Neck collar. Unlike head surface cooling, chilled neck collars aim to cool the arterial
blood that supplies the brain tissue. There are several prototypes on the market. The feasibility
of this approach for inducing selective brain hypothermia has been evaluated theoretically by
researchers over the past 10 years. The major blood vessels in the neck region can be modeled as
straight tubes embedded in the neck cylinder. Theoretical simulation showed limited temperature
reductions (<1 C) along the carotid arteries even when the neck surface temperature was reduced
to 0 C (145). The limitation on cooling predicted in this study is largely due to the deep locations
of the carotid arteries. Temperature reduction along the arteries depends on not only the length
of the cooling collar but also on the blood ow rate of the arteries. This model was later modied
to include the vertebral arteries owing to their relatively supercial locations and their small
blood ow rates (146). Depending on the cooling collar temperature, up to 37 W of heat could
be removed from the arterial and venous blood in the neck region. Although the theoretical
analysis failed to demonstrate signicant potential for a neck collar to reduce brain temperature,
it did indicate that the cooling collar has the potential to decrease the body temperature by as
much as 0.69 C h1 by cooling blood ow through the supercial jugular vein. Therefore, the
neck collars small size and portable nature may make it suitable to provide an initial downward
trend in the body temperature while a patient is transported to the hospital.
6.4.3. Interstitial cooling in the neck. Considering that the tissue between the cold neck surface
and an embedded blood vessel is the major thermal barrier for effective removal of heat from the
arterial blood, an interstitial cooling device was proposed to bypass the barrier. Wang & Zhu
(147) rst proposed inserting a cooling device into the neck muscle to ensure close physical
contact with the arterial blood, thereby enhancing the contact surface area. The advantages of this
approach include the small size of the thermal source device, its powerful cooling capacity, fast
cooling capability, and adjustable rewarming rate. The physical principle of the cooling approach
was demonstrated by the theoretical simulations of the neck and head temperature elds. The
simulations predicated a reduction in the temperature of the common carotid arterial blood by
at least 2 C within 30 min. A prototype of the device was tested independently in a rat model by
two research groups. Wang et al. (148) used a small version of that proposed by Wang & Zhu
(147) and inserted it into the neck muscle of adult rats. Unlike head surface cooling, this device
produces a nearly uniform temperature eld in the rat brain tissue because the chilled arterial
blood is circulating throughout the brain structure, where it exerts a convective cooling effect
(148). A similar experiment was performed by Wei et al. (149) to not only monitor the brain
temperature reduction but also test whether it reduces the infarct volume in the brain tissue.
Both the incidence of peri-infarct depolarization and infarct volume were reduced by more than
70% (149). Both experimental studies demonstrated the feasibility and efcacy of this approach
in small animal models. Large animal models are needed to evaluate the safety and effectiveness
of the technique.
149
ARI
16 June 2009
7:14
6.4.4. Intracarotid flushing. Because most of the noninvasive cooling methods are not effective
in reducing the brain temperature quickly, more aggressive techniques have been suggested. By
adapting the approach of veno-venous blood cooling, researchers have proposed selective cooling
of only the blood supply to the brain. Because cold saline infusion is able to produce a relatively
fast cooling rate in the whole body, infusing cold saline via a catheter inserted into the femoral
vessels and advanced to the carotid artery should have considerable potential for achieving rapid
brain cooling. Several theoretical studies were performed to evaluate the clinical feasibility of this
approach. On the basis of a three-dimensional (3D) mathematical model developed by Neimark
et al. (150), it was shown that an infusion ow rate of 30 ml min1 is sufcient to induce moderate
brain cooling within 10 min in the brain, after which hypothermia can be maintained. A fast cooling
rate (4 C 10 min1 ) was observed when 6 ml cold saline was infused to the middle cerebral artery
in a rat model (151). In this study, brain cooling signicantly improved the motor behavior of the
tested rats; however, reduction in the infarct volume was not substantial. Because a rat brain is
much smaller than a human brain, the cooling extent and rate for the rat experiments may not
be applied directly to the humans. Although the theoretical models have provided proof of the
principle, future experimental study on large animals and clinical trials are needed to examine the
feasibility of this technique.

ANRV382-BE11-06
6.4.5. Intraparenchymal cooling. Given that thermal conduction resistance between the skin
and core tissue is the major factor that affects the effectiveness of surface cooling of the brain,
inserting a cooling device directly into the brain tissue may address the limitation. A recent patent
by neurosurgeons and researchers at the University of Chicago and Argonne National Laboratory
describes such a cooling probe. The cooling device consists of a 2.5 cm long, dual-lumen stainless
steel shaft with cold water circulating from a slurry ice bath to the device. The diameter of the
device is approximately <2.7 mm.
A recently published paper (152) analyzes the temperature distribution in the brain tissue
surrounding the intraparenchymal cooling device. The temperature of the device surface can be
lowered to 6 C with a circulating ice-slurry solution. The theoretical simulation illustrated how
the cooling eld penetrates into the brain tissue. One important factor is the local blood perfusion
rate, which is well known to be as high as 0.0133 s1 . The effect of blood perfusion will limit
the zone of inuence of the cooling device, because the cooled blood is rapidly redistributed
and diluted throughout the entire blood circulation. In contrast, in clinical settings where brain
perfusion is either not present at all (e.g., the ischemic core within a brain infarction) or markedly
reduced (e.g., penumbra region around an ischemic brain core), both the blood perfusion rate
and the temperature will have a reduced counteracting inuence on the probe, thus allowing the
cooling zone to extend further laterally from the device when compared with the cooling of a
noninjured brain. Depending on the extent of blood perfusion, cooling penetration achieved by
the probe ranged from 10 to 25 mm, with a larger cooling penetration being obtained in injured
(less perfused) brain regions. A major advantage of the device is the potential for fast cooling. Final
steady state of therapeutic hypothermia can be achieved in less than 16 min after probe insertion.
One of the major concerns of the device is patient safety, because the proposed approach is
too invasively aggressive to be applied in many therapeutic scenarios. The inventor argues that
the device can be used side by side with other routine neuro-critical-care procedures, including
insertion of both rigid and exible catheters to drain ventricular uid, as well as the use of probes
to monitor cerebral pressures. If these catheters are inserted via a small hole drilled in the skull, it is
conceivable that modications of those catheters to include the cooling device can be implemented
with no added risk or complication.
150
Diller
Zhu
ANRV382-BE11-06
ARI
16 June 2009
7:14
7. ENGINEERING CONTRIBUTIONS IN BRAIN HYPOTHERMIA

7.1. Development of Cooling Devices

The major contribution of engineering in therapeutic brain hypothermia is to design reliable and
safe devices to achieve target cooling rates and temperatures. New technologies are typically evaluated for thermal efcacy and safety in small and large animal models to determine their suitability
for testing in humans. During the design, patient safety is a prime consideration, including issues
such as leakage of coolant, induced freezing damage to tissue, physical trauma, etc. Sterilizability,
size minimization consistent with thermal performance requirements, and physical packaging are
typical design considerations during the development of the device.
In general, there are two categories of device designs that are used clinically for therapeutic hypothermia: skin surface and endovascular cooling. More than six companies (Medivance, MTRE,
Seabrook, Cincinnati SubZero, Birchbrook, and Garnar) manufacture surface cooling devices such
as cooling blankets, garments, helmets, and pads. This category of devices is based on noninvasive
methods and, to date, has been most broadly applied in clinical trials. An alternative approach is
presented by AVACore in which an applied negative pressure to glabrous skin in conjunction with
cooling is used to enhance blood perfusion through arteriovenous anastomoses, thereby increasing
convective energy transport with the body core. This technique has the potential for providing
much faster cooling rates. There are three companies (Radiant Medical, Innercool Therapies, and
Alsius) that have developed endovascular catheters for cooling human blood as it ows past the
device when inserted into a large vessel. Endovascular cooling is superior in providing a fast cooling rate; however, its major drawbacks are blood clogging and clotting, invasive surgical insertion
procedures, and complications associated with whole-body cooling. Other approaches, such as
intracarotid cooling and interstitial cooling in the neck, are in their infant stage and are yet to be
tested in large animal models and clinical studies.
7.2. Mathematical Simulations of Cooling and Rewarming Processes

In the past two decades, clinicians have realized the importance of closely monitoring brain temperature during hypothermia. Even a small reduction in brain temperature can improve neurological
outcomes of patients suffering brain injury. Temperature variation within normothermic brain
tissue is usually very small; however, especially during therapeutic hypothermia, temperature gradients can develop not only between brain and core but also within regions of the brain (38, 53,
118, 153155). Information on internal temperature gradients is difcult to obtain clinically by
measurement with temperature probes owing to the risk of inducing additional tissue damage.
Current noninvasive temperature measurements such as magnetic resonance imaging ( 2 C)
lack the desired resolution to monitor small temperature variations in the brain region. Therefore, analytical methods for understanding the transient and spatial temperature distribution in
brain tissue during hypothermia therapy are clinically valuable.
Quantitative thermal modeling aids in identication of an optimal treatment protocol, and with
appropriate constitutive input data, affords the opportunity for designing personalized therapeutic
regimens. Theoretical modeling provides clinicians with powerful tools to improve the ability to
deliver safe and effective therapy. Most importantly, thermal modeling permits the identication
and evaluation of critical monitoring sites to assess the cooling extent and to assure patient safety.
Most of the current theoretical thermal models in brain hypothermia implement the Pennes
bioheat equation (156) that simplies the thermal contribution of local blood vessels as a simple
heat source term added to the traditional heat conduction equation (110, 142, 147, 150, 152,
151
ARI
16 June 2009
7:14
157161). With the advancement in computational resources, researchers have the capability to
simulate the 3D temperature eld of the head and neck and to consider multiple large blood vessels
individually in the model. When point-to-point temperature nonuniformities are important, a
model that incorporates perfusion through the vasculature is necessary to predict accurately the
tissue temperature eld; however, because of the complex vascular geometry, one may model only
selected large blood vessels individually and neglect the others. There were several attempts in
the past to model large blood vessels, including the carotid arteries and jugular veins in the neck,
during brain hypothermia (145147, 162). In those studies, temperature decay along the large
arteries was used to evaluate whether various techniques could induce sufcient cooling to the
arterial blood supplied to the brain. Owing to the complicated vascular structure, it is difcult to
model effects of individual blood vessels in the brain region. Van Leeuwen et al. (163) predicted
temperature contours based on a detailed vasculature in the brain and found that they agree very
well with those predicted by the Pennes model. This may be mainly due to the large rate and diffuse
pattern of blood perfusion in the brain tissue, for which the Pennes bioheat equation is a preferred
approach. Advanced computational methods also allow researchers to model the head with a more
realistic geometry than a simple hemisphere structure. The head geometry is usually based on
magnetic resonance images (MRIs), which can be imported into grid-generating algorithms and
then be interfaced with numerical software for temperature simulation (157, 159, 163). However,
the results obtained from the more complicated head models to date are very similar to those
predicted by a simple, layered head geometry.
One of the major challenges in mathematic simulation of cooling and rewarming processes
is assessment of local blood perfusion variations in response to cooling. In most theoretical simulations, blood perfusion is usually considered a constant during cooling or is considered to be
decreasing as a function of the local tissue temperature following the Q10 law (164, 165). The
predicted temperature distribution in the brain is in agreement with the observed temperature
eld during steady state; however, there is a large discrepancy between theory and experiment on
how long it takes to establish a steady state during cooling and rewarming.
In an experimental study performed on a rat model during head surface cooling, thermocouples were inserted into the brain to monitor the temperature reduction and recovery (111). The
measured characteristic time to establish a steady state varied from 5 min to longer than 40 min,
whereas the theoretical simulation predicted a much smaller characteristic time (less than 5 min)
for the small size of the rat head, when the blood ow rate is unchanged during the simulation.
These results imply that the change of the blood perfusion rate in tissue contributes signicantly
to the characteristic transient time. A similar conclusion can be drawn from other animal models
(152) and alternative cooling approaches (148).
The Q10 law represents a linear relationship between 1/T, where T is tissue temperature, and
log CMRO2 (the cerebral metabolic rate of oxygen consumption). A mathematical expression of
this relationship is given by

ANRV382-BE11-06
Tt 37
CMRO2 = CMRO2,n Q 1010 ,
(1)
where CMRO2,n is the normal cerebral metabolic rate of oxygen consumption, and Q10 is a constant
factor, which has been reported (165) to vary between 2 and 4.4 based on correlations with
experimental measurements. This law states that the metabolic rate decreases by a factor of Q10
with each 10 C reduction in temperature. Based on a Q10 value of 2, it has been calculated
that hypothermia decreases cerebral metabolic rate by an average value of 7% for the rst 1 C
reduction in temperature, whereas metabolic rate is reduced to one-half of the normal value
when the temperature reduction is 10 C. This type of relation is analogous to the Arrhenius
equation. During normal conditions, cerebral blood ow (CBF) may follow the same pattern
152
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
as that of cerebral metabolism owing to their direct coupling. Several temperature simulations
have incorporated the Q10 law (110, 152, 157, 158). Because the local blood perfusion keeps
decreasing with the temperature during cooling, the temperature eld from the cold surface can
penetrate more readily into the deep brain region, which, in turn, would further trigger perfusion
reduction. If the temperature dependence of perfusion progresses during cooling, the result would
be an extended time to reach a steady state.
During cerebral ischemia or head injury, not only may the Q10 value change but also CBF
may be decoupled from metabolism. A number of studies have examined the variation of CBF
during systemic hypothermia. Using the radioactive microsphere technique, Busija & Lefer (166)
measured CBF in anesthetized newborn pigs. They concluded that systemic hypothermia reduced
CBF secondarily to the depression of cerebral metabolic rate. Verhaegen et al. (167) measured the
cortical blood ow in anesthetized rats using a laser Doppler owmeter (LDF) and found that CBF
was reduced during moderate hypothermia. Okubo et al. (168) examined the effect of systemic
cooling on cerebral metabolism and regional CBF variation in newborn piglets. They measured
the regional CBF with colored microspheres and demonstrated that a reduction of cerebral cortex
temperature resulted in a decrease in the blood ow in all brain regions. Unlike many experimental
studies on CBF response during systemic cooling, there have been only a few studies on the effect
of selective brain cooling on CBF, and the various results are inconsistent. Laptook et al. (141)
examined the differences of CBF in newborn swine during selective brain cooling versus wholebody cooling and illustrated that the global CBF was reduced during both whole-body cooling
and selective brain cooling. Ibayashi et al. (169) demonstrated that the regional CBF decreased
when selective brain cooling was implemented on rats. However, a previous study (170) using the
LDF technique showed that the cortical CBF in normal lightly anesthetized rats increased during
selective brain cooling.
LDF has been used to monitor blood perfusion in supercial areas of the brain. To measure
the blood perfusion rate of brain tissue, the LDF probe must be inserted into the brain to have
access to the measured region because its sensing signal cannot penetrate the skull. Another limitation of LDF is that it may not be suitable for measuring global blood ow changes in the
brain. Microspheres of a selected diameter, a standard and popular technique for measuring local blood perfusion rate in tissue, are injected into blood and allowed to circulate freely until
they become lodged in the smaller capillaries. It is possible to determine the blood perfusion at
different times using different colored and sized microspheres introduced serially into the circulation. However, the microsphere can provide only a low temporal resolution. In previous studies
(53, 171, 172), CBF was measured only once or twice during hypothermia in the animal models. More recently, MRI has been used to detect the cerebral perfusion in animal models during
brain hypothermia (16). Because of the relatively long acquisition time for a 3D MRI scan, the
technique may not be suitable for studying the response of blood perfusion during cooling. It
has also been proposed that the variation of the blood ow rate of the common carotid artery
should be considered as an index of the global CBF and how it changes during brain hypothermia should also be considered (111). It is estimated that more than 80% of the blood supplied
to the brain is from the common carotid arteries. The blood ow rate of the common carotid
artery can be measured continuously using an LDF applied in an in vivo setting to study the
transient behavior of temperature and blood ow responses during selective brain cooling and
rewarming (111). Very similar transient proles of the brain temperature and blood ow rate
of the common carotid artery as characterized by their characteristic time constants were observed in rats (111). Nonetheless, more rigorous experimental verication is needed to establish
the correlation between the CBF and blood ow rate of the common carotid artery. The accuracy of theoretical simulations is still questionable unless the simulations can be veried with
153
ANRV382-BE11-06
ARI
16 June 2009
7:14
experimental data that continuously monitor the local blood perfusion rate during cooling and
rewarming.
8. OPPORTUNITIES FOR BIOMEDICAL

ENGINEERING CONTRIBUTIONS

As the mechanistic basis of the therapeutic application of hypothermia for ischemic brain injury
improves and becomes more complete, it may become possible to accurately and predictably design
treatment protocols to achieve specic outcomes. For example, there is an accumulating body of
evidence that points to the need for a rapid reduction in brain temperature following a trauma
event in order to realize the potential benet of hypothermia therapy. The minimum temperature
drop is thought to be at least 2 C, and the window of opportunity in which it can be effective is
limited to 90 min or less. Quick initiation of rapid cooling is apparently an essential feature of
hypothermic therapy. The practical implementation of rapid brain cooling would benet greatly
from a cooling process that could be started in the eld by rst responders for whom specialized
training and skilled procedure requirements are minimal. Further, the requirement for cooling
the brain at a rate of 1.5 C h1 or higher imposes limitations on the types of technology that
can be used for removing heat rapidly from the interior of the body. The combined criteria of
simple, safe, and fast cooling dene the considerations facing biomedical engineers in designing
new devices and procedures.
Recent advances by thermal physiologists have opened an opportunity for achieving the rapid
cooling of the body thermal core (79, 91, 172, 173). Their technology uses an applied negative
pressure on glabrous skin to mechanically distend arteriovenous anastomoses, thereby greatly
increasing the cutaneous blood perfusion. By diverting a signicant fraction of the cardiac output
to the skin, where there can be an effective heat transfer with the environment, it is possible to
use the circulatory system as a convective conduit for thermal energy between the body surface
and the thermal core, including the brain. In initial studies with humans, it has been possible to
achieve rates of change of core temperature of 10 C h1 and higher, which would be adequate for
hypothermia induction in cases of TBI. One concern raised by neurosurgeons is decrease in blood
pressure, which can be dangerous to patients with compromised health. Although this technology
may not be suitable for clinical applications in hypothermia, it illustrates that there are possibilities
for extending the currently limited performance range of technologies into the domain in which
methods of hypothermia therapy could be made available for widespread adoption.
SUMMARY POINTS
1. Hypothermia has a documented efcacy in treating tissues subjected to ischemic stress,
including complications of TBI and stroke as well as cardiac arrest.
2. The magnitude of hypothermia necessary to derive its prophylactic benet is not dened
clearly, although there are indications that it may as little as 2 C to a brain temperature
of 35 C.
3. Clinical evidence is accumulating that shows time is of the essence for implementing
hypothermia in the target tissue. The window of opportunity appears to be 90 min or
less. However, the treatment window may be wider if the cooling is prolonged.
4. Although rapid cooling to a state of hypothermia is demonstrated to be of direct benet,
it is important to avoid rapid rewarming from hypothermia.
154
Diller
Zhu
ANRV382-BE11-06
ARI
16 June 2009
7:14
FUTURE ISSUES
1. The therapeutic mechanism of action of hypothermia is not well understood, and therefore the ability to design treatment protocols for optimal efcacy is compromised. Although the problem is quite challenging, it presents a major opportunity for signicant
contributions.

2. Effective cooling of the brain remains a major difculty in the practical use of hypothermia. Engineering methodologies should play a key role in identifying new and effective
technologies and devices and adapting them for clinical application.
3. It is widely held that treatment of brain ischemia requires a quick reduction in temperature
of the affected tissue to a state of mild hypothermia, possibly within an hour of the
precipitating event, in order to achieve full neuroprotective benet. New methods and
devices are needed to quickly and safely produce mild hypothermia of the brain by
minimally skilled personnel in a eld environment.
DISCLOSURE STATEMENT
The authors are not aware of any biases that might be perceived as affecting the objectivity of this
review.
ACKNOWLEDGMENTS
Preparation of this review was supported in part by the Robert M. and Prudie Leibrock Endowed
Professorship in Engineering at the University of Texas at Austin and the State of Maryland
TEDCO fund.
LITERATURE CITED
1. Wass CT, Lanier WL, Hofer RE, Scheithauer BW, Andrews AG. 1995. Temperature changes of 1 C
alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia.
Anesthesiology 83:32535
2. Bigelow WG, Callaghan JC, Hopps VA. 1950. General hypothermia for experimental intracardiac
surgery: use of articial pacemaker for cardiac standstill and cardiac rewarming in general hypothermia. Ann. Surg. 132:53143
3. Drake CG, Jory TA. 1962. Hypothermia in the treatment of critical head injury. Can. Med. Assoc. J.
87:88791
4. Fay T. 1945. Observations on generalized refrigeration in cases of severe cerebral trauma. Res. Publ.
Assoc. Res. Nerv. Dis. 4:61119
5. Kabat H. 1940. The greater resistance of very young animals to arrest of the brain circulation. Am. J.
Physiol. 122:58899
6. Lazorthes G, Campan L. 1958. Hypothermia in the treatment of craniocerebral traumatism. J. Neurosurg.
15:16267
7. Miller JA. 1949. Factors in neonatal resistance to anoxia. I. Temperature and survival of newborn guinea
pigs under anoxia. Science 110:11314
8. Sedzimir CB. 1959. Therapeutic hypothermia in cases of head injury. J. Neurosurg. 16:40714
9. Vandam DV, Burnap TK. 1959. Hypothermia (part 1). N. Engl. J. Med. 261:54653
10. Vandam DV, Burnap TK. 1959. Hypothermia (part 2). N. Engl. J. Med. 261:595603
155
ARI
16 June 2009
7:14
11. Safar P. 2002. Cerebral resuscitation from temporary complete global brain ischemia. In Cerebral Blood
Flow: Mechanisms of Ischemia, Diagnosis and Therapy, ed. MR Pinsky, pp. 10636. Berlin/Heidelberg:
Springer-Verlag
12. Rosomoff HL. 2004. Historical review of the development of brain hypothermia. In Hypothermia for
Acute Brain Damage: Pathomechanism and Practical Aspects, ed. N Hayashi, R Bullock, DW Dietrich,
T Maekawa, A Tamura, pp. 316. New York: Springer
13. Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, et al. 2001. Lack of effect of induction of
hypothermia after acute brain injury. N. Engl. J. Med. 344:55663
14. Maier CM, Sun GH, Cheng D, Yenari MA, Chan PH, Steinberg GK. 2002. Effects of mild hypothermia
on superoxide anion production, superoxide dismutase expression, and activity following transient focal
cerebral ischemia. Neurobiol. Dis. 11:2842
15. Marion DW, Leonov Y, Ginsberg M, Katz LM, Kochanek PM, et al. 1996. Resuscitative hypothermia.
Crit. Care Med. 24(Suppl.):S81-89
16. Yenari MA, Onley D, Hedehus M, deCrespigny A, Sun GH, et al. 2000. Diffusion- and perfusionweighted magnetic resonance imaging of focal cerebral ischemia and cortical spreading depression under
conditions of mild hypothermia. Brain Res. 885:20819
17. Xu L, Yenari MA, Steinberg GK, Giffard RG. 2002. Mild hypothermia reduces apoptosis of mouse
neurons in vitro early in the cascade. J. Cereb. Blood Flow Metab. 22:2128
18. McIntyre LA, Fergusson DA, Hebert PC, Moher D, Hutchison JS. 2003. Prolonged therapeutic
hypothermia after traumatic brain injury in adults: a systematic review. JAMA 289:299299
19. Clifton GL, Allen S, Barrodale P, Plenger P, Berry J, et al. 1993. A phase II study of moderate hypothermia
in severe brain injury. J. Neurotrauma 10:26371
20. Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, et al. 2002. Hypothermia on admission in
patients with severe brain injury. J. Neurotrauma 19:293301
21. Clifton GL. 2004. Is keeping cool still hot? An update on hypothermia in brain injury. Curr. Opin. Crit.
Care 7:11619
22. Markgraf CG, Clifton GL, Moody MR. 2001. Treatment window for hypothermia in brain injury.
J. Neurosurg. 95:97983
23. Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, et al. 1997. Treatment of traumatic
brain injury with moderate hypothermia. N. Engl. J. Med. 336:54046
24. Metz C, Holzschuh M, Bein T, Woertgen C, Frey A, et al. 1996. Moderate hypothermia in patients with
severe head injury: cerebral and extracerebral effects. J. Neurosurg. 85:53341
25. Shiozaki T, Sugimoto H, Taneda M, Yoshida H, Iwai A, et al. 1993. Effect of mild hypothermia on
uncontrollable intracranial hypertension after severe head injury. J. Neurosurg. 79:36368
26. Jiang JY, Yu MK, Zhu C. 2000. Effect of long-term mild hypothermia therapy in patients with severe
traumatic brain injury: 1-year follow-up review of 87 cases. J. Neurosurg. 93:54649
27. Safar P, Kochanek PM. 2001. Comments on Lack of effect of induction of hypothermia after acute
brain injury. N. Engl. J. Med. 345:66
28. Gal R, Cundrle I, Zimova I, Smrcka M. 2002. Mild hypothermia therapy for patients with severe brain
injury. Clin. Neurol. Neurosurg. 104:31821
29. Qiu W, Liu W, Shen H, Wang W, Zhang Z, et al. 2005. Therapeutic effect of mild hypothermia on
severe traumatic head injury. Chin. J. Traumatol. 8:2732
30. Liu WG, Qiu WS, Zhang Y, Wang WM, Lu F, Yang XF. 2006. Effects of selective brain cooling in
patients with severe traumatic brain injury: a preliminary study. J. Int. Med. Res. 34(1):5864
31. Peterson K, Carson S, Carney N. 2008. Hypothermia treatment for traumatic brain injury: a systematic
review and meta-analysis. J. Neurotrauma 25:6271
32. Guidelines for the management of severe traumatic brain injury, 3rd ed. 2007. J. Neurotrauma 24:S1108
33. Van Der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR. 2007. Hypothermia in animal
models of acute ischemic stroke: a systematic review and meta-analysis. Brain 130:306374
34. Brint S, Jacewicz M, Kiessling M, Tanabe J, Pulsinelli W. 1988. Focal brain ischemia in the rat: methods
for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral
common carotid arteries. J. Cereb. Blood Flow Metab. 8:47485

ANRV382-BE11-06
156
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
35. Barone FC, Feuerstein GZ, White RF. 1997. Brain cooling during transient focal ischemia provides
complete neuroprotection. Neurosci. Biobehav. Rev. 21:3144
36. Kurasako T, Zhan L, Pulsinelli WA, Nowak TS. 2003. Transient cooling during early reperfusion
attenuates delayed edema and infarct progression in the spontaneously hypertensive rat. Distribution
and time course of regional brain temperature change in a model of postischemic hypothermic protection.
J. Cereb. Blood Flow Metab. 27:191930
37. Morikawa E, Ginsberg MD, Dietrich WD, Duncan RC, Kraydieh S, et al. 1992. The signicance of
brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery
occlusion in the rat. J. Cereb. Blood Flow Metab. 12(3):38089
38. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. 1998. Moderate hypothermia in the
treatment of patients with severe middle cerebral artery infarction. Stroke 29:246166
39. Schwab S, Schwarz S, Aschoff A, Keller E, Hacke W. 1998. Moderate hypothermia and brain temperature
in patients with severe middle cerebral artery infarction. Acta Neurochir. 71(Suppl.):13134
40. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. 2001. Feasibility
and safety of moderate hypothermia after massive hemispheric infarction. Stroke 32(9):203335
41. Berrouschot J, Sterker M, Bettin S, Koster J, Schneider D. 1998. Mortality of space-occupying (malignant ) middle cerebral artery infarction under conservative intensive care. Intensive Care Med. 24:62023
42. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. 1996. Malignant middle
cerebral artery territory infarction: clinical course and prognostic signs. Arch. Neurol. 53:30915
43. Kammersgaard LP, Rasmussen BH, Jorgensen HS, Reith J, Weber U, Olsen TS. 2000. Feasibility and
safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a
case-control study. Stroke 31:225156
44. Kasner SE, Wein T, Piryawat P, Villar-Cordove CE, Chalela JA, et al. 2002. Acetaminophen for altering
body temperature in acute stroke: a randomized clinical trial. Editorial comment: a randomized clinical
trial. Stroke 33:13035
45. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, et al. 2005. Whole-body hypothermia for neonates with hypoxicischemic encephalopathy. N. Engl. J. Med. 353:157484
46. de Georgia MA, Krieger DW, Abou-Chebl A, Devlin TG, Jauss M, et al. 2004. Cooling for acute
ischemic brain damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 63:31217
47. Krieger DW, De Georgia MA, Abou-Chebl A, Andrefsky JC, Sila CA, et al. 2001. Cooling for acute
ischemic brain damage (COOL AID): an open pilot study of induced hypothermia in acute ischemic
stroke. Stroke 32:184154
48. Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, et al. 1996. Adverse cerebral
outcomes after coronary bypass surgery. Multicenter study of Perioperative Ischemia Research Group
and the Ischemia Research and Education Foundation investigators. N. Engl. J. Med. 335:185763
49. Miller JH. 1993. Partial replacement of an infected arterial graft by a new prosthetic polytetrauoroethylene segment: a new therapeutic option. J. Vasc. Surg. 17(3):54658
50. Nussmeier NA. 2002. A review of risk factors for adverse neurologic outcome after cardiac surgery. J.
Extracorpor. Technol. 34:410
51. Levin S, Payan H. 1966. Effects of ischemia and other procedures on the brain and retina of the gerbil
(Meriones unguiculatus). Exp. Neurol. 16(3):25562
52. Polderman KH. 2004. Keeping a cool head: how to induce and maintain hypothermia. Crit. Care Med.
32(12):255860
53. Busto R, Dietrich WD, Globus MY-T, Valdes I, Scheinberg P, Ginsberg MD. 1987. Small differences
in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J. Cereb.
Blood Flow Metab. 7:72938
54. Nurse S, Corbett D. 1994. Direct measurement of brain temperature during and after intraischemic hypothermia: correlation with behavioral, physiological, and histological endpoints. J. Neurosci.
14(12):772634
55. Minawisawa H, Nordstrom CH, Smith ML, Siesjo BK. 1990. The inuence of mild body and brain
hypothermia on ischemic brain damage. J. Cereb. Blood Flow Metab. 10(3):36574
157
ARI
16 June 2009
7:14
56. Gillinov AM, Bator JM, Zehr KJ, Redmond JM, Burch RM, et al. 1993. Neutrophil adhesion molecule
expression during cardiopulmonary bypass with bubble and membrane oxygenators. Ann. Thorac. Surg.
56(4):84753
57. Zeiner A, Muellner M, Frossard M, Janata K, Behringer W, et al. 1996. Mild therapeutic hypothermia
to improve neurological outcome after cardiac arresta pilot study. Circulation 94:I9-10
58. Zeiner A, Mullner M, Sterz F, Frossard M, Laggner A. 1996. Mild resuscitative therapeutic hypothermia
after cardiac arrest and its inuence on hemodynamic parameters. Crit. Care Med. 24:A115
59. Sterz F, Safar P, Tisherman S, Radovsky A, Kuboyama K, Oku K. 1991. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit. Care Med. 19:37989
60. Moyer DJ, Welsh FA, Zager EL. 1992. Spontaneous cerebral hypothermia diminishes focal infarction
in rat brain. Stroke 23(12):181216
61. Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, et al. 2003. Coronary
endarterectomy: experience and lessons learned in 1500 cases. Ann. Thorac. Surg. 76(5):145762
62. Kouchoukos NT, Daily BB, Wareing TH, Murphy SF. 1994. Hypothermic circulatory arrest for cerebral
protection during combined carotid and cardiac surgery in patients with bilateral carotid artery disease.
Ann. Surg. 219(6):699705
63. Bernard SA, Gray TW, Buist MD, Jones BM, Silverster W, et al. 2002. Treatment of comatose survivors
of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 346:55763
64. Hypothermia After Cardiac Arrest Study Group. 2002. Mild therapeutic hypothermia to improve the
neurologic outcome after cardiac arrest. N. Engl. J. Med. 346:54656.
65. Wagner KR, Zuccarello M. 2005. Local brain hypothermia for neuroprotection in stroke treatment and
aneurysm repair. Neurol. Res. 27:23845
66. Davis FA, Jacobson S. 1971. Altered thermal sensitivity in injured and demyelinated nervea possible
model of the temperature effect in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 34:55161
67. Waxman SG. 1982. Membranes, myelin and the pathophysiology of multiple sclerosis. N. Engl. J. Med.
306:152933
68. Barres AB, Raff MC. 1993. Proliferation of oligodendrocyte precursor cells depends on electrical activities
in axons. Nature 361:25860
69. Shi J, Marinovich A, Barres BA. 1998. Purication and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J. Neurosci. 18:462736
70. van Diemen HAM, van Dongen MMMM, Dammers JWHH, Polman CH. 1992. Increased visual impairment after exercise (Uhthoffs phenomenon) in multiple sclerosis: therapeutic possibilities. Eur. Neurol.
32:23134.
71. Coyle PK, Krupp LB, Doscher C, Deng Z, Milazzo A. 1996. Clinical and immunological effects of
cooling in multiple sclerosis. Neurorehab. Neural Repair 10:915
72. Feys P, Helsen W, Liu X, Mooren D, Albrecht H, et al. 2004. Effects of peripheral cooling on intention
tremor in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 76:37379
73. Comi G, Leocani L. 2002. Assessment, pathophysiology and treatment of fatigue in multiple sclerosis.
Expert Rev. Neurother. 2:86767
74. Gutierrez GM, Chow JW, Tillman MD, McCoy SC, Castellano V, White LJ. 2005. Resistance training
improves gait kinematics in persons with multiple sclerosis. Arch. Phys. Med. Rehabil. 86:182429
75. Newman MA, Dawes H, Van Den Berg M, Wade DT, Burridge J, Izadi H. 2007. Can aerobic treadmill
training reduce the effort of walking and fatigue in people with multiple sclerosis: a pilot study. Mult.
Scler. 13(1):11319
76. Pariser G, Madras D, Weiss E. 2006. Outcomes of an aquatic exercise program including aerobic capacity,
lactate threshold, and fatigue in two individuals with multiple sclerosis. J. Neurol. Phys. Ther. 30(2):8290
77. Roehrs TG, Karst GM. 2004. Effects of an aquatics exercise program on quality of life measures for
individuals with progressive multiple sclerosis. J. Neurol. Phys. Ther. 28(2):6371
78. White LJ, Dressendorfer RH. 2004. Exercise and multiple sclerosis. Sports Med. 34(15):1077100
79. Grahn D, Murray JvLS, Heller HC. 2008. Cooling via one hand improves physical performance in
heat-sensitive individuals with multiple sclerosis: a preliminary study. BMC Neurol. 8:14
80. Hemon D, Jougla E. 2004. The heat wave in France in August 2003. Rev. Epidemiol. Sante Publique 52:35

ANRV382-BE11-06
158
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
81. Bouchama A, Knochel JP. 2002. Heat stroke. N. Engl. J. Med. 346:197888
82. Armstrong LE, Crago AE, Adams R, Roberts WO, Marech CM. 1996. Whole-body cooling of hyperthermic runners: comparison of two eld therapies. Am. J. Emerg. Med. 14:35558
83. Khogali M, Weiner JS. 1980. Heat stroke: report on 18 cases. Lancet 2:27678
84. Khogali M, al Khawashki M. 1981. Heat stroke during the Makkah pilgrimage. Saudi Med. J. 2:8593
85. Graham BS, Lichtenstein MJ, Hinson JM, Theil GB. 1986. Nonexertional heatstroke. Physiologic
management and cooling in 14 patients. Arch. Intern. Med. 146:8790
86. Al-Harthi SS, Yaqub BA, Al-Nozha MM. 1986. Management of heat stroke patients by rapid cooling at
Mecca pilgrimage. Saudi Med. J. 7:369
87. Bouchama A, Dehbi M, Chaves-Carballo E. 2007. Cooling and hemodynamic management in heatstroke:
practical recommendations. Crit. Care 11:R54
88. Proulx CI, Ducharme MB, Kenny GP. 2006. Safe cooling limits from exercise-induced hyperthermia.
Eur. J. Appl. Physiol. 96(4):43445
89. Vicario SJ, Okabajue R, Haltom T. 1986. Rapid cooling in classic heat stroke: effects on mortality rates.
Am. J. Emerg. Med. 4:39498
90. Shibolet S, Coll R, Gilat T, Sohar E. 1967. Heatstroke: its clinical picture and mechanism in 36 cases.
Q. J. Med. 36:52548
91. Grahn DA, Cao VH, Heller HC. 2005. Heat extraction through the palm of one hand improves aerobic
exercise endurance in a hot environment. J. Appl. Physiol. 99:97278
92. Dietrich WD, Prado R, Halley M, Watson BD. 1993. Microvascular and neuronal consequences of common carotid artery thrombosis and platelet embolization in rats. J. Neuropathol. Exp. Neurol. 52(4):35160
93. Welsh FA, Sims RE, Harris VA. 1990. Mild hypothermia prevents ischemic injury in gerbil hippocampus.
J. Cereb. Blood Flow Metab. 10:55763
94. Colbourne F, Corbett D. 1995. Delayed postischemic hypothermia: a six month survival study using
behavioral and histological assessments of neuroprotection. J. Neurosci. 15:725060
95. Markgraf CG, Clifton GL, Moody MR. 2001. Treatment window for hypothermia in brain injury.
J. Neurosurg. 95:97983
96. Wolff B, Machill K, Schumacher D, Schulzki I, Werner D. 2008. Early achievement of mild therapeutic
hypothermia and the neurologic outcome after cardiac arrest. Int. J. Cardiol. Epub ahead of print
97. Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM. 2000. Prolonged but delayed postischemic
hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J. Cereb.
Blood Flow Metab. 20(12):17028
98. Corbett D, Hamilton M, Colbourne F. 2000. Persistent neuroprotection with prolonged postischemic
hypothermia in adult rats subjected to transient middle cerebral artery occlusion. Exp. Neurol. 163:2006
99. Kirkpatrick AW, Chun R, Brown R, Simons RK. 1999. Hypothermia and the trauma patient. Trauma
Crit. Care 42:33343
100. Michenfelder J. 1988. Protecting the Brain. In Anesthesia and the Brain. Clinical, Functional, Metabolic and
Vascular Correlates, ed. J Michenfelder, pp. 18193, USA: Churchill Livingstone. 1st ed.
101. Tisherman SA, Rodriguez A, Safar P. 1999. Therapeutic hypothermia in traumatology. Surg. Clin. North
Am. 79:126989
102. Chambers S. 1999. Induced hypothermia for head injury. Nurs. Crit. Care 4:11216
103. Mouritzen CV, Anderson MN. 1966. Mechanisms of ventricular brillation during hypothermia: relative
change in myocardial refractory period and conduction velocity. J. Thorac. Cardiovasc. Surg. 51:57984
104. Frank SM, Beattie C, Christopherson R, et al. 1993. Unintentional hypothermia is associated with
postoperative myocardial ischemia. Anesthesiology 78:46876
105. Rohrer MJ, Natale AM. 1992. Effect of hypothermia on the coagulation cascade. Crit. Care Med. 20:1402
5
106. Bohn DJ, Biggar WD, Smith CR, Conn AW, Baker GA. 1986. Inuence of hypothermia, barbiturate
therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning. Crit. Care
Med. 14:52934
107. Gunn AJ, Gunn TR. 1998. The pharmacology of neuronal rescue with cerebral hypothermia. Early
Hum. Dev. 53:1935
159
ARI
16 June 2009
7:14
108. Dirnagl U, Iadecola C, Moskowitz MA. 1999. Pathobiology of ischemia stroke: an integrated view. Trends
Neurosci. 22:39197
109. Iwata O, Thornton JS, Sellwood MW, Iwata S, Sakata Y, et al. 2005. Depth of delayed cooling alters
neuroprotection pattern after hypoxia-ischemia. Ann. Neurol. 58:7587
110. Diao C, Zhu L, Wang H. 2003. Cooling and rewarming for brain ischemia or injury: theoretical analysis.
Ann. Biomed. Eng. 31:34653
111. Diao C, Zhu L. 2006. Temperature distribution and blood ow response in rat brain during selective
brain cooling. Med. Phys. 33:256573
112. Thoresen M, Wyatt J. 1997. Keeping a cool head, posthypoxic hypothermiaan old idea revisited. Acta
Paediatr. 86:102933
113. Schubert A. 1995. Side effects of mild hypothermia. J. Neurosurg. Anesthesiol. 7(2):13947
114. Wang H, Olivero W, Lanzino G, Elkins W, Rose J, et al. 2004. Rapid and selective cerebral hypothermia
achieved using a cooling helmet. J. Neurosurg. 100:27277
115. Mayer S, Kowalski RG, Presciutti M, Ostapkovich ND, McGann E, et al. 2004. Clinical trial of a novel
surface cooling system for fever control in neurocritical care patients. Crit. Care Med. 32(12):250825
116. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass T, et al. 2005. Moderate hypothermia in
neonatal encephalopathy: efcacy outcomes. Pediatr. Neurol. 32:1117
117. Olsen TS, Weber UJ, Kammersgaard LP. 2003. Therapeutic hypothermia for acute stroke. Lancet Neurol.
2:41016
118. Schwab S, Spranger M, Aschoff A, Steiner T, Hacke W. 1997. Brain temperature monitoring and
modulation in patients with severe MCA infarction. Neurology 48:76267
119. Dae MW, Gao DW, Ursell PC, Stillson CA, Sessler DI. 2003. Safety and efcacy of endovascular cooling
and rewarming for induction and reversal of hypothermia in human-sized pigs. Stroke 34:73438
120. Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, et al. 2002. Induction of mild systemic
hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute
myocardial infarction. J. Am. Coll. Cardiol. 40:192834
121. Doufas AG, Akca O, Barry A, Petrusca DA, Suleman M, et al. 2002. Initial experience with a novel
heat-exchanging catheter in neurosurgical patients. Anesthesiol. Analg. 95:175256
122. Georgiadia D, Schwarz S, Kollmar R, Schwab S. 2001. Endovascular cooling for moderate hypothermia
in patients with acute stroke: rst results of a novel approach. Stroke 32:255053
123. Inderbitzen B, Yon S, Lasheras J, Dobak J, Perl J, Steinberg GK. 2002. Safety and performance of a
novel intravascular catheter for inducing and reversal of hypothermia in a porcine model. Neurosurgery
50:36470
124. Mack WJ, Huang J, Winfree C, Kim G, Oppermann M, et al. 2003. Ultrarapid, convection-enhanced
intravascular hypothermia: a feasibility study in nonhuman primate stroke. Stroke 34:199499
125. Holzer M, Behringer W, Janata A, Bayegan K, Schima H, et al. 2005. Extracorporeal venovenous cooling
for induction of mild hypothermia in human-sized swine. Crit. Care Med. 33:134650
126. Holzer M, Marcus Mullner

M, Sterz F, Robak O, Kliegel A, et al. 2006. Efcacy and safety of endovascular
cooling after cardiac arrest: cohort study and bayesian approach. Stroke 37:179297
127. Keller E, Imhof H-G, Gasser S, Terzic A, Yonekawa Y. 2003. Endovascular cooling with heat exchange
catheters: a new method to induce and maintain hypothermia. Intensive Care Med. 29:93943
128. Lyden PD, Allgren RL, Ng K, Akins P, Meyer B, et al. 2005. Intravascular cooling in the treatment of
stroke (ICTuS): early clinical experience. J. Stroke Cerebrovasc. Dis. 14(3):10714
129. vanden Hoek TL, Kasza KE, Beiser DG, Abella BS, Franklin JE, et al. 2004. Induced hypothermia by
central venous infusion: saline ice slurry vs chilled saline. Crit. Care Med. 32:S42531
130. Virkkunen I, Yli-Hankala A, Silfvast T. 2004. Induction of therapeutic hypothermia after cardiac arrest
in prehospital patients using ice-cold Ringers solution: a pilot study. Resuscitation 62(3):299302
131. Rosengart AJ, Zhu L, Schappeler T, Goldenberg FD. 2009. Fever control in hospitalized stroke patients
using simple intravenous uid regimensa theoretical evaluation. J. Clin. Neurosci. 16(1):5155
132. Badjatia N, Bodock M, Guanci M, Rordorf GA. 2006. Rapid infusion of cold saline (4 C) as adjunctive
treatment of fever in patients with brain injury. Neurology 66:173941

ANRV382-BE11-06
160
Diller
Zhu

ANRV382-BE11-06
ARI
16 June 2009
7:14
133. Kliegel A, Losert H, Sterz F, Kliegel M, Holzer M, et al. 2005. Cold simple intravenous infusions
preceding special endovascular cooling for faster induction of mild hypothermia after cardiac arresta
feasibility study. Resuscitation 64:34751
134. Bernard S, Rosalion A. 2008. Therapeutic hypothermia induced during cardiopulmonary resuscitation
using large-volume, ice-cold intravenous uid. Resuscitation 76:31113
135. Lopez M, Sessler DI, Walter K, Emerick T, Ozaki M. 1994. Rate and gender dependence of the sweating,
vasoconstriction, and shivering threshold in humans. Anesthesiology 80:78088
136. Frank SM, Raja SN, Bulcao CF. 1999. Relative contribution of core and cutaneous temperatures to
thermal comfort and autonomic responses in humans. J. Appl. Physiol. 86:158893
137. Frank SM, Satitpunwaycha P, Bruce SR, Herscovitch P, Goldstein DS. 2003. Increased myocardial
perfusion and sympathoadrenal activation during mild core hypothermia in awake humans. Clin. Sci.
104:5038
138. Noguchi Y, Nishio S, Kawuchi M, Asari S, Ohmoto T. 2002. A new method of inducing selective brain
hypothermia with saline perfusion into the subdural space: effects on transient cerebral ischemia in cats.
Acta Med. Okayama 56:27986
139. Ku Y, Montgomery LD, Webbon B. 1996. Hemodynamic and thermal responses to head and neck
cooling in men and woman. Am. J. Phys. Med. Rehabil. 75:44350
140. Bakken HE, Kawasaki H, Oya H, Greenlee JDW, Howard MA. 2003. A device for cooling localized
regions of human cerebral cortex. J. Neurosurg. 99:6048
141. Laptook AR, Shalak L, Corbett RJT. 2001. Differences in brain temperature and cerebral blood ow
during selective head vs whole-body cooling. Pediatrics 108(5):110310
142. Zhu L, Diao C. 2001. Theoretical simulation of temperature distribution in the brain during mild
hypothermia treatment for brain injury. Med. Biol. Eng. Comput. 39:68187
143. Gelman B, Schleien CL, Lohe A, Kuluz JW. 1996. Selective brain cooling in infant piglets after cardiac
arrest and resuscitation. Crit. Care Med. 24:100917
144. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, et al. 2005. Selective head cooling
with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial. Lancet
365:66370
145. Bommadevera M, Zhu L. 2002. Temperature difference between the body core and the arterial blood
supplied to the brain during hyperthermia or hypothermia in humans. Biomech. Model. Mechanobiol.
1(2):13749
146. Eginton ML. 2007. Evaluation of the effectiveness of a commercial cooling collar in reducing body temperature
during heat stress: theoretical modeling of body temperature distribution. MS thesis, University of Maryland,
Baltimore County, pp. 155.
147. Wang Y, Zhu L. 2007. Selective brain hypothermia induced by an interstitial cooling device in human
neck: theoretical analyses. Eur. J. Appl. Physiol. 101(1):3140
148. Wang Y, Zhu L, Rosengart AJ. 2008. Targeted brain hypothermia induced by an interstitial cooling
device in the rat neck: experimental study and model validation. Int. J. Heat Mass Transf. 51:566270
149. Wei G, Hartings JA, Tortella FC, Lu XM. 2008. Extraluminal cooling of bilateral common carotid
arteries as a method to achieve selective brain cooling for neuroprotection. J. Neurotrauma 25:54960
150. Neimark MA, Konstas A, Choi JH, Laine AF, Pile-Spellman J. 2008. Brain cooling maintenance with
cooling cap following induction with intracarotid cold saline infusion: a quantitative model. J. Theor.
Biol. 253(2):33344
151. Ding Y, Li J, Luan X, Lai Q, McAllister JP, et al. 2004. Local saline infusion into ischemic territory
induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion.
Neurosurgery 54:95665
152. Zhu L, Rosengart AJ. 2008. Cooling penetration into normal and injured brain via intraparenchymal
brain cooling probe: theoretical analyses. Heat Transf. Eng. 29(3):28494
153. Mellergard P, Nordstrom C, Christensson M. 1990. A method for monitoring intracerebral temperature
in neurosurgical patients. Neurosurgery 27:65457
154. Stone JG, Young WL, Smith CR, Solomon RA, Wald A, et al. 1995. Do standard monitoring sites
reect true brain temperature when profound hypothermia is rapidly induced and reversed? Anesthesiology
82:34451
161
ARI
16 June 2009
7:14
155. Wass CT, Lanier WL. 1996. Hypothermia-associated protection from ischemic brain injury: implications
for patient management. Int. Anesthesiol. Clin. 34(4):95111
156. Pennes HH. 1948. Analysis of tissue and arterial blood temperatures in the resting human forearm.
J. Appl. Physiol. 1:93122
157. Dennis BH, Eberhart RC, Dulikravich GS, Radons SW. 2003. Finite element simulation of cooling of
realistic 3-D human head and neck. J. Biomech. Eng. 125:83240
158. Janssen FEM, van Leeuwen GMJ, van Steenhoven AA. 2005. Modeling of temperature and perfusion
during scalp cooling. Phys. Med. Biol. 50(17):406573
159. Ley O, Bayazitoglu Y. 2003. Effect of physiology on the temperature distribution of a layered head with
external convection. Int. J. Heat Mass Transf. 46(17):323341
160. Ley O, Bayazitoglu Y. 2004. Temperature distribution in a realistic human head during selective
and whole body cooling and during circulatory arrest. Proc. IMECE, IMECE2004-60733, Nov. 1319,
Anaheim, California
161. Zhu L, Schappeler T, Cordero-Tumangday C, Rosengart AJ. 2009. Thermal interactions between
blood and tissue: development of a theoretical approach in predicting body temperature during blood
cooling/rewarming. In Advances in Numerical Heat Transfer, Vol. 3, ed. WJ Minkowycz, EM Sparrow,
pp. 197-219. CRC Press, Taylor and Francis Group. 400 pp.
162. Zhu L. 2000. Theoretical evaluation of contributions of both radial heat conduction and countercurrent
heat exchange in selective brain cooling in humans. Ann. Biomed. Eng. 28:26977
163. van Leeuwen GMJ, Hand J, Lagendijk JW, Azzopardi V, Edwards AD. 2000. Numerical modeling of
temperature distributions within the neonatal head. Pediatr. Res. 48:35156
164. Bering E. 1961. Effect of body temperature change on cerebral oxygen consumption of the intact monkey.
Am. J. Physiol. 200:41719
165. Hoffman W, Miletich DJ, Albrecht R. 1982. Differential cerebral hypothermia. Cryobiology 19:392401
166. Busija DW, Lefer CW. 1987. Hypothermia reduces cerebral metabolic rate and cerebral blood ow in
newborn pigs. Am. J. Physiol. 253:H86973
167. Verhaegen MJJ, Todd MM, Hindman BJ, Warner DS. 1993. Cerebral autoregulation during moderate
hypothermia in rats. Stroke 24:40714
168. Okubo K, Itoh S, Isobe K, Kusaka T, Nagano K, et al. 2001. Cerebral metabolism and regional blood
ow during moderate systemic cooling in newborn piglets. Pediatr. Int. 43:496501
169. Ibayashi S, Kakano K, Ooboshi H, Kitazono T. 2000. Effect of selective brain hypothermia on regional
cerebral blood ow and tissue metabolism using brain thermo-regulator in spontaneously hypertensive
rats. Neurochem. Res. 25:36975
170. Kuluz JW, Prado R, Chang J, Ginsberg MD, Schleien CL, Busto R. 1993. Selective brain cooling
increases cortical cerebral blood ow in rats. Am. J. Physiol. 265:H82427
171. Rudy LW, Boucher JK, Edmunds H. 1972. The effect of deep hypothermia and circulatory arrest on
the distribution of systemic blood ow in rhesus monkeys. J. Thorac. Cardiovasc. Surg. 64:70613
172. Enomoto S, Hindman BJ, Dexter F, Smith T, Cutkomp J. 1996. Rapid rewarming causes an increase in the
cerebral metabolic rate for oxygen that is temporarily unmatched by cerebral blood ow. Anesthesiology
84:13921400
173. Grahn DA, Brock-Utne JG, Watenpaugh DE, Heller HC. 1998. Recovery from mild hypothermia can
be accelerated by mechanically distending blood vessels in the hand. J. Appl. Physiol. 85:164348

ANRV382-BE11-06
RELATED REVIEWS
1. Crawshaw, LI. 1980. Temperature regulation in vertebrates. Annu. Rev. Physiol. 42:47391
2. Baker, MA. 1982. Brain cooling in endotherms in heat and exercise. Annu. Rev. Physiol. 44:8596
162
Diller
Zhu
AR382-FM
ARI
26 May 2009
14:3

Contents
Annual Review of
Biomedical
Engineering
Volume 11, 2009
Implanted Neural Interfaces: Biochallenges and Engineered Solutions

Warren M. Grill, Sharon E. Norman, and Ravi V. Bellamkonda p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Fluorescent Probes for Live-Cell RNA Detection
Gang Bao, Won Jong Rhee, and Andrew Tsourkas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
Proteomics by Mass Spectrometry: Approaches, Advances,
and Applications
John R. Yates, Cristian I. Ruse, and Aleksey Nakorchevsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
The Inuence of Muscle Physiology and Advanced Technology
on Sports Performance
Richard R. Neptune, Craig P. McGowan, and John M. Fiandt p p p p p p p p p p p p p p p p p p p p p p p p p p p p81
Patient-Specic Modeling of Cardiovascular Mechanics
C.A. Taylor and C.A. Figueroa p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 109
Hypothermia Therapy for Brain Injury
Kenneth R. Diller and Liang Zhu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 135
On the Biomechanics of Vaginal Birth and Common Sequelae
James A. Ashton-Miller and John O.L. DeLancey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 163
Cancer Cells in Transit: The Vascular Interactions of Tumor Cells
Konstantinos Konstantopoulos and Susan N. Thomas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 177
Microengineered Platforms for Cell Mechanobiology
Deok-Ho Kim, Pak Kin Wong, Jungyul Park, Andre Levchenko, and Yu Sun p p p p p p p p p p 203
Living-Cell Microarrays
Martin L. Yarmush and Kevin R. King p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 235
Cell Mechanics: Dissecting the Physical Responses of Cells to Force
Brenton D. Hoffman and John C. Crocker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 259
Bioengineering Challenges for Heart Valve Tissue Engineering
Michael S. Sacks, Frederick J. Schoen, and John E. Mayer, Jr. p p p p p p p p p p p p p p p p p p p p p p p p p p 289

Hypothermia Therapy

Transféré par

Informations du document

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Hypothermia Therapy

Transféré par

Droits d'auteur :

Formats disponibles

ANRV382-BE11-06

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Click here for quick links to

Department of Biomedical Engineering, The University of Texas, Austin, Texas 78712;

Department of Mechanical Engineering, The University of Maryland, Baltimore,

Annu. Rev. Biomed. Eng. 2009. 11:13562

First published online as a Review in Advance on

hypothermia, neurological trauma, brain cooling, head injury, ischemia,

The Annual Review of Biomedical Engineering is

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

1. HISTORY OF HYPOTHERMIA TREATMENT IN MEDICINE . . . . . . . . . . . . . .

1. HISTORY OF HYPOTHERMIA TREATMENT IN MEDICINE

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

2. BIOLOGICAL AND CHEMICAL REACTIONS TO INJURY

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

TBI: traumatic brain

3. NEUROPROTECTIVE MECHANISMS ASSOCIATED

4. APPLICATIONS WITH IMPROVED CLINICAL OUTCOMES

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

4.2. Brain Ischemic Injury from Stroke

ischemia. Neuroprotection by hypothermia is more prominent in lower-temperature (28 C and

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

4.3. Brain Ischemic Injury during Surgery

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

4.4. Multiple Sclerosis

4.5. Heat Stroke

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

5. FACTORS AFFECTING THE PROTECTIVE OUTCOMES

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

5.2. Cooling Extent

5.3. Cooling Duration

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

5.4. Rewarming Rate

6. CURRENTLY USED BRAIN HYPOTHERMIA APPROACHES

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

6.2. Whole-Body versus Selective Brain Cooling

6.3. Whole-Body Hypothermia

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

6.3.2. Blood cooling

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

6.4. Selective Brain Cooling

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

7. ENGINEERING CONTRIBUTIONS IN BRAIN HYPOTHERMIA

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

7.1. Development of Cooling Devices

7.2. Mathematical Simulations of Cooling and Rewarming Processes

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

CMRO2 = CMRO2,n Q 1010 ,

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

8. OPPORTUNITIES FOR BIOMEDICAL

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

126. Holzer M, Marcus Mullner

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Annu. Rev. Biomed. Eng. 2009.11:135-162. Downloaded from arjournals.annualreviews.org

Implanted Neural Interfaces: Biochallenges and Engineered Solutions