ANRV382-BE11-06 ARI 16 June 2009 7:14

Hypothermia Therapyfor Brain InjuryKenneth R. Diller1 and Liang Zhu2

1Department of Biomedical Engineering, The University of Texas, Austin, Texas 78712;email: kdiller@mail.utexas.edu2Department of Mechanical Engineering, The University of Maryland, Baltimore,Maryland 21250

Annu. Rev. Biomed. Eng. 2009. 11:135–62

First published online as a Review in Advance onApril 13, 2009

The Annual Review of Biomedical Engineering isonline at bioeng.annualreviews.org

This article’s doi:10.1146/annurev-bioeng-061008-124908

Copyright c© 2009 by Annual Reviews.All rights reserved

1523-9829/09/0815-0135$20.00

Key Words

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

AbstractInduced hypothermia is an acknowledged useful therapy for treating con-ditions that lead to cell and tissue damage caused by ischemia, includingtraumatic brain injury, stroke, and cardiac arrest. An accumulating body ofclinical evidence, together with several decades of research, has documentedthat the efficacy of hypothermia is dependent on achieving a reduced temper-ature in the target tissue before or soon following the ischemia-precipitatingevent. The temperature must be lowered to within a rather small range ofvalues to effect therapeutic benefit without introducing collateral problems.Rewarming must be much slower than cooling. Many different methods anddevices have been used for cooling, with mixed results. There are existingopportunities for bioengineers to improve our understanding of the mecha-nisms of hypothermia and to develop more effective methods of cooling thebrain following trauma.

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Hypothermia: statein which the body coretemperature is reducedat least 2◦C below thenormothermia value(37◦C)

Ischemia: restrictionin blood supply, withresultant damage tothe affected tissue

Contents

1. HISTORY OF HYPOTHERMIA TREATMENT IN MEDICINE . . . . . . . . . . . . . . 1362. BIOLOGICAL AND CHEMICAL REACTIONS TO INJURY

IN THE HUMAN BRAIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373. NEUROPROTECTIVE MECHANISMS ASSOCIATED

WITH BRAIN HYPOTHERMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1384. APPLICATIONS WITH IMPROVED CLINICAL OUTCOMES

BY BRAIN HYPOTHERMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1384.1. Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1384.2. Brain Ischemic Injury from Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394.3. Brain Ischemic Injury during Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1404.4. Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1414.5. Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

5. FACTORS AFFECTING THE PROTECTIVE OUTCOMES ASSOCIATEDWITH BRAIN HYPOTHERMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425.1. Time of Cooling Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425.2. Cooling Extent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435.3. Cooling Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445.4. Rewarming Rate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

6. CURRENTLY USED BRAIN HYPOTHERMIA APPROACHES . . . . . . . . . . . . . . . 1446.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1446.2. Whole-Body versus Selective Brain Cooling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456.3. Whole-Body Hypothermia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456.4. Selective Brain Cooling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

7. ENGINEERING CONTRIBUTIONS IN BRAIN HYPOTHERMIA . . . . . . . . . . . 1517.1. Development of Cooling Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1517.2. Mathematical Simulations of Cooling and Rewarming Processes . . . . . . . . . . . . . . 151

8. OPPORTUNITIES FOR BIOMEDICALENGINEERING CONTRIBUTIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

1. HISTORY OF HYPOTHERMIA TREATMENT IN MEDICINE

Cooling processes have been applied in medicine since ancient Greece. Over the interveningmillennia, developing an understanding of the function of the human thermoregulatory systemhas been a subject of great interest, and eventually attempts were made to manipulate it fortherapeutic applications. During Nepoleon’s invasion of Russia, French surgeons noticed that thesoldiers left in snow had a better survival rate that those with a warm blanket. During and followingWorld War II, devices were developed for the explicit purpose of removing heat from the bodycore via surface cooling garments that were worn by airplane pilots and astronauts. The availabilityof cooling garments provided a method for inducing hypothermia (or avoiding hyperthermia) witha greater level of control than afforded by more passive techniques such as whole-body immersioninto cold water or ice baths.

It is well documented that unconsciousness occurs within 15 s after complete occlusion ofcerebral arteries and that brain tissue cannot recover fully after only 5 min of normothermic brainischemia (1). Induced hypothermia has been studied as a means to protect the brain from ischemia

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Hypoxia: deficiencyof oxygen in tissues

since the 1940s (2–10). Resuscitative cerebral hypothermia was introduced first in cardiac arrest forcerebral resuscitation in the 1950s (11). Later research focused on maximization of the ability of thebrain tissue to survive anoxic no-flow states as enhanced by hypothermia. In the 1960s and 1970s,animal experiments and clinical studies showed the benefits of hypothermia in prolonging the braintime-tolerance to cardiac arrest. Hypothermia was also implemented in open-chest and open-heartsurgeries, including intracranial aneurysm clipping and arteriovenous malformation resection tominimize injury to the heart and brain. Cardiopulmonary bypass was usually employed for patientsundergoing neurovascular surgical procedures, to allow for a bloodless field for the surgeon and tolesson the risk of hemorrhage. Bypass in conjunction with induced hypothermia provides cardiacsurgeons sufficient time for many procedures while avoiding permanent brain injury. The surgicalinterruption 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 significantly to reduced mortality associatedwith previously inoperable cardiac and cerebral pathology. Most of the neuroprotective effectshave been more evident in animal experiments than in patients.

Because early studies commonly used deep states of hypothermia ≤30◦C, it is not surpris-ing that many years of experimentation were required to identify the therapeutic bounds forwhich hypothermia presents a clear efficacy. Research in hypothermia to enhance brain tissuerecovery after ischemic attack became dormant in the 1970s and the 1980s owing to thermalmanagement difficulties and uncertainty of benefits as well as detrimental systemic complicationsassociated with deep hypothermia. The idea of mild hypothermia has been re-investigated byresearchers since 1987 owing to encouraging animal experiments on canine, swine, and rodentmodels. Because of the ability to better control the state of hypothermia in animals, extensiveexperimentation on such models has been conducted to evaluate effects of cooling methods, tem-perature depression, hypothermia duration, cooling initiation relative to the ischemic event, andrewarming rate on the brain recovery from ischemia. There is a large amount of experimental ev-idence of hypothermia-induced neuroprotection from ischemia injury in laboratory animals. Theneuroprotective mechanisms of hyperthermia have become increasingly better understood in thepast two decades. Supporting data in human subjects are still limited, especially for randomizedmulticenter clinical trials (13). In clinical studies, hypothermia therapy seems more successful inopen-heart and neck surgery than in traumatic head injury. This is not unexpected, because ini-tiating cooling before ischemia attack has been demonstrated to maximize the benefits conferredby hypothermia, although delay in initiation by 2 h or more has also shown limited benefits inboth animal models and clinical studies. These foregoing studies in brain hypothermia have setthe stage for future investigations to develop more effective and well-controlled approaches fortreating brain ischemia. It is anticipated that hypothermia will be proven as an effective methodto limit and eliminate injury and death associated with brain ischemia, to the benefit of a largepatient population.

2. BIOLOGICAL AND CHEMICAL REACTIONS TO INJURYIN THE HUMAN BRAIN

Brain ischemia can be the result of ischemic stroke, cardiovascular and respiratory disorders, andexternal physical trauma. If the initial damage is limited, the brain may be able to recover. Ifthe injury is extensive, secondary brain damage occurs, including intracranial hypertension (brainswelling), hemorrhage, hypoxia, and edema. It is well known that brain oxygen stores becomeexhausted 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 andcascades initiated by the trauma will then follow. Those cascade events evolve gradually and may last

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Reperfusion:reestablishing of bloodflow in a vascular bedfollowing a period ofischemia

TBI: traumatic braininjury

several days after the initial trauma. Increase in extracellular K+, energy depletion, disruption of theblood-brain barrier, free radical release, excitotoxicity, and inflammation are typical consequencesof those cascade events. Loss of selective neurons following global or local brain ischemia maylead to permanent neurologic deficit and even death.

3. NEUROPROTECTIVE MECHANISMS ASSOCIATEDWITH 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 expen-ditures of cerebral metabolic rates of glucose and oxygen. Brain oxygen consumption can decreaseby approximately 5–7% for every degree Celsius decrease in tissue temperature. However, theimproved outcomes associated with mild hypothermia suggest that it may play a role in deterringdeleterious biochemical actions following brain injury (14–16). Hypothermia retards progressionof the ischemia cascade and pathologic neuroexcitation. The major mechanisms of neuropro-tection by hypothermia are attenuation in the opening of the blood-brain barrier, reduction ofglutamate release, alleviation of inflammation, and slowing of free radical generation and release.It may impair glutamate-mediated calcium influx or directly inhibit calcium-mediated effects oncalcium/calmodulin kinase. As a result, hypothermia preserves high-energy phosphates that mayfacilitate the maintenance of membrane integrity during ischemia, limit edema formation, lowerintracranial pressure, and interrupt necrosis and apoptosis (17). All of the mechanisms lead to longneuronal survival and improve outcomes after reperfusion.

4. APPLICATIONS WITH IMPROVED CLINICAL OUTCOMESBY BRAIN HYPOTHERMIA

4.1. Traumatic Brain Injury

Traumatic brain injury (TBI) is a nondegenerative, noncongenital insult to the brain tissue due toexternally inflicted 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 notconsistent. There is marked heterogeneity among available clinical studies. In 1994, a multicenter,randomized, prospective phase III study of systemic hypothermia in severe brain injury, involvingseven medical centers in the United States (13), was initiated based on the promise of decades ofsomewhat sporadic experiments and anecdotal positive clinical outcomes for hypothermia used totreat TBI in addition to an extensive phase II clinical trial (19). This study enrolled 392 patients,ages 16–65, who suffered coma from brain injury in the absence of other major traumas. A controlgroup received standard management with a nominal core temperature of 37◦C. The treatmentgroup received the same management protocol at a target temperature of 33◦C. There was a largevariation in the cooling induction time due to many individual circumstances. The cooling processbegan 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 over18 h. Some of the patients were already hypothermic (≤35◦C) owing to independent circumstanceson admission to the hospital and were retained in a treatment subgroup. Overall, a very minimaldifference was observed between the treatment and control groups (13), with the exception ofthe subgroup, already hypothermic at admission, which had significantly better outcomes (20).

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Although the results of this study were discouraging, they led directly to an enhanced appreciationfor 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 forTBI.

Several clinical studies (23–25) tested hypothermia therapy in patients with severe head injuryand achieved improved outcomes compared with normothermia groups. Hypothermia benefitswere evident in patients with a coma score of 5–6 at months 3 and 6 (23). It is reported that morethan 62% of patients achieved good outcome in the hypothermia group versus 39% in the controlgroup. Jiang et al. (26) evaluated the long-term benefits of hypothermia in patients with severetraumatic head injury. It was found that mortality decreased by 40%, and the rate of favorableoutcome increased by 70% in the hypothermia group one year after the head injury. One ofthe common benefits identified in the above studies was a marked reduction of the intracranialpressure in the hypothermia group after days of treatment. It was recommended that coolingshould 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 benefits by hypothermia tothe 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 goodneurological outcome in the hypothermia group, suggested certain methodological discrepanciesin the Clifton study. The latest clinical trial of hypothermia on traumatic head injury (29) showedimproved 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 hypothermiatreatment, with complications that were manageable. A recent review by Peterson et al. (31) ofhypothermia-related neuroprotection on TBI patients identifies a cooling duration longer than48 h as a favorable factor; however, it cautions the risk of pneumonia. Based on the review, thestrong evidence of the long-term (more than one year) benefits of hypothermia suggests followingup 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 thebenefits and safety of brain hypothermia for traumatic head injury patients. In the third editionof the Guidelines for the Management of Severe Traumatic Brain Injury, issued by the BrainTrauma Foundation in 2007, it is stated that mild hypothermia should be exercised with cautionfor patients with TBI (32).

4.2. Brain Ischemic Injury from Stroke

The 2005 Guidelines on Acute Stroke Treatment by the American Stroke Association identifyhypothermia after stroke as a promising field of research. A recent review by van der Worpet al. (33) concludes that hypothermia improved outcomes of animals suffering from ischemicstroke 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 viaocclusion of the distal middle cerebral and ipsilateral common carotid arteries than of focal brainischemia, for which it is more difficult to define experimental conditions. Computerized images ofcerebral infarct volume and edema are commonly used to evaluate ischemic damage to the braintissue. If the animals are kept alive after the injury, cognitive evaluation is conducted to assessthe long-term protective outcome of cooling. The efficacy of hypothermia is better with lowertarget temperature (35) and/or when initiated before or during the onset of ischemia. A studyby Kurasako et al. (36) on a spontaneously hypertensive rat model demonstrated a strong, lineartemperature-dependent reduction in infarct volume and edema progression in transient focal

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ischemia. Neuroprotection by hypothermia is more prominent in lower-temperature (28◦C and30◦C) groups. More improvements are found in temporary than in permanent ischemic models(35, 37).

There are limited clinical trials to test the efficacy and safety of various hypothermia approachesfor acute ischemic stroke patients. Clinical studies by Schwab et al. (38–40) showed that morethan 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 theclinical studies were not conducted using a control group, the observed 38% mortality rate ismuch lower than a typical death rate of 70% in severe stroke patients (41, 42). A small clinicaltrial by Kammersgaard et al. (43) that used mild hypothermia (35◦C) in 17 patients also showedmarked improvement of mortality rate, from 23% in controls to 12%. Unlike the Schwab studiesassociated with many serious systemic complications, including thrombocytopenia, bradycardia,and pneumonia, the only reported side effect in the Kammersgaard trial was shivering, which wastreated by pethidine. Kasner et al. (44) conducted a clinical trial with mild hypothermia inducedby acetaminophen administration in an attempt to achieve brain cooling rapidly. The results wereinconclusive because acetaminophen produced only a very mild state of hypothermia, <36.5◦C,bringing question to its clinical efficacy. A randomized trial of hypothermia in infants with hypoxic-ischemic encephalopathy showed reduced risk of death or disability (45); however, neuroprotectionfrom hypothermia was not obvious in another two clinical studies (46, 47), although the resultsfavored hypothermia.

4.3. Brain Ischemic Injury during Surgery

Cardiopulmonary bypass–related brain injury is a common postsurgical observation. A multi-center study by Roach et al. (48) demonstrated that more than 6% of patients suffered adverseneurological outcomes after coronary artery bypass grafting. Neuropsychological deficits (cogni-tive 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 aconsequence of hypoperfusion. Early experimental studies on animals suggested that brain tissueremained partially ischemic after resuscitation from circulatory arrest, and delayed ischemia wasobserved during the following hours. In both intracardiac and extracardiac surgeries, formationof emboli is the major factor contributing to most neurological complications (50). Animal andclinical studies showed that some patients developed severe neurological deficits after surgeries in-volving unilateral common carotid occlusion (51). The deficits were attributed to lack of posteriorcommunicating arteries following carotid occlusion.

The main effects of brain hypothermia include decrease in intracranial pressures and cerebraledema, reduction of tissue oxygen demands, and amelioration of numerous deleterious cellularbiochemical mechanisms, including calcium shift, excitotoxicity, lipid peroxidation and other freeradical reactions, DNA damage, and inflammation (52). Hypothermia during experimental cere-bral ischemia provides potent, dose-related and long-lasting neuroprotection (53, 54). Conversely,an elevated brain temperature of only 1–2◦C strikingly worsens experimental neuronal injury andclinical outcome (55). Experimental studies have shown that brain hypothermia enhances thebrain’s tolerance to ischemia and thereby improves neurological outcomes. Therapeutic mild hy-pothermia was implemented as a standard therapy in the international resuscitation guidelines.Several animal studies (56–58) have been performed to assess neuro-deficit score in dogs afterbypass surgery. Profound brain hypothermia improved significantly the neuro-deficit score of thecontrol group (48.3) to 19.2 in the cooling group (0 = normal and 100 = brain dead). Improved

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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 by75%. Mild brain hypothermia was reported to minimize cerebral impairment in 1500 patients un-dergoing pulmonary endarterectomy (61). The protective effect of hypothermia was also evidentin patients undergoing carotid endarterectomy (62), wherein there were no early postoperativestrokes or reversible ischemic neurological deficits following the surgery. Two randomized clinicaltrials in large groups of patients with global cerebral ischemia after cardiac arrest reported thatthe number of patients with good outcome increased at least 40% in the hypothermic group, al-though the mortality rate was similar in both groups (63, 64). Recently, an FDA-approved coolingsystem (ChillerPadTM and ChillerStripTM System, Seacoast Technologies, Inc., Portsmouth, NH)was employed in a clinical trial of aneurysm repair, and hypothermia markedly reduced vasogenicedema and protected the blood-brain barrier (65). However, this technology only superficiallycools 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 myelinsurrounding 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 getworse when the body temperature is even slightly elevated. Early experiments using in vitropreparations of demyelinated nerves (66, 67) demonstrated that a small increase in temperatureshortened the duration of the action potential, and the available current was insufficient to excitethe ranvier node connecting myeline sheath cells. Since demyelination may lead to conductionblock, disuse, and finally cell death, an increase in neuronal activity by decreasing nerve tem-perature can, in theory, prolong the action potential duration and induce sufficient current todepolarize the ranvier node. Studies have shown that the restored neuronal activities may leadto proliferation, migration, and maturation of myelin-producing cells (68, 69). Therefore, cool-ing has the potential to slow the progression of multiple sclerosis by fostering remyelination andprotecting the axon from degeneration.

There are several types of body cooling garments, based on heat removal from the surfacevia evaporation, ice pack, or refrigeration, that are available to this patient population. Most MSpatients using a lightweight cooling vest found that the symptoms were alleviated (70). A coldbath or swimming also provides better management of heat-related symptoms. In a controlledexperiment, improvements in acuity, timed walk and muscle strength, and reduction in cytokineproduction were demonstrated in a cooling group when compared with controls (71). Local-ized cooling on the wrist and forearm while keeping the heart rate and body core temperatureunchanged illustrated a clear reduction of overall tremor amplitude and frequency during a step-tracking task in MS patients (72). Aerobic exercise is usually recommended to mild-to-modest MSpatients because it provides fitness and psychological benefits similar to those in a healthy subject,including increased strength and endurance, reduced depression, increased positive moods, andimproved cardiovascular fitness (73–78). However, exercise will lead to a rapid increase in bodytemperature, which compromises the patients’ ability to function. The detrimental effects of bodytemperature increase can be offset by cooling before or during exercise. A new device that enableshighly effective heat removal from the body core reduces exercise-related heat stress and therebyincreases the physical performance capacity of heat-sensitive individuals with MS (79). As a conse-quence, cooling may help MS patients gain greater independence and may improve their qualityof life.

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4.5. Heat Stroke

Heat exhaustion and heat stroke are the most common heat-related diseases involving dysfunctionand/or failure of temperature control in the human body. They usually occur when the body is sub-jected to elevated ambient temperature and during strenuous exercise. When body hyperthermialasts 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 stroke–related deaths are reported in the United States annually. Heat strokeresulted 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-systemdysfunction (81). There are several approaches for rapidly cooling the body after the onset of heatstroke. The first steps are always moving the patient to a cool place away from environmental heatsources and removing excess clothing. Internal cooling approaches include water irrigation lavageor an intravascular catheter. External cooling can be produced with convection or conductionsources applied to the skin surface. Internal methods are obviously more invasive than externalmethods, are usually associated with collateral risks, and may cause water intoxication in patientswith compromised health. Some external methods aim to promote evaporative cooling on the skinsurface via spraying tepid water and/or using fans to increase air circulation (82–86). Unfortu-nately, these methods tend to be counterproductive because they promote vasoconstriction, whichincreases the thermal resistance between the body core and the skin surface, where heat can berejected to the environment. The median time for evaporative cooling to achieve a target rectaltemperature of 38◦C varies widely with the presenting state of hyperthermia and is often well overan hour. This method has limited efficacy if the humidity of the surrounding environment is nearsaturation. Other external cooling techniques are accomplished by increasing the temperaturegradient 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 icedwater is messy and poorly tolerated, and it does not allow attachment of some types of moni-toring equipment. The challenge in implementing the conduction method is to prevent the skintemperature from falling below 30◦C to trigger shivering. Numerous studies have demonstratedthe detrimental effects of vasoconstriction and shivering on patients. Vasoconstriction results indecreased cutaneous blood perfusion, which impedes convective heat transfer from the body coreto the skin and therefore, compromises the body’s ability to lose heat fast. The application ofcooling to the surface of glabrous skin in which the arteriovenous anastomoses are distended andflowing enables blood circulation to the body core to provide an effective convective pathway forrejection of core heat in thermally stressed indiciduals (91).

5. FACTORS AFFECTING THE PROTECTIVE OUTCOMESASSOCIATED WITH BRAIN HYPOTHERMIA

5.1. Time of Cooling Initiation

Numerous controlled animal experiments have demonstrated the benefit of initiation of coolingbefore the brain injury to confer significant neuroprotective outcomes. Of course, precooling is anoption only for circumstances under which the onset of brain ischemia is foreseen. Precooling is aclinical option for open-heart and neck surgery. Experimental data from a rat model demonstratedthe greatest benefits of neuroprotection when hypothermia was induced during global ischemia(92). Initiation of hypothermia before the injury completely prevented secondary brain damagein gerbils (93).

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For all the other clinical applications involving human subjects, precooling is not usually pos-sible. The general consensus is to initiate brain hypothermia as early as possible following anischemia-precipitating event, although some studies have shown neuroprotective effects evenwhen the treatment was delayed by up to 6 h (94). Brain injury mechanisms typically progressrapidly within 3–6 h after the initial injury. Hypothermia can reduce the initial inflammatory re-sponse after head trauma so as to minimize or prevent secondary brain injury. It is well acceptedthat there is a 1–2 h treatment window for animal models, after which the benefits of hypothermiaare strongly diminished. However, it is difficult to correlate rodent data directly to humans. On thebasis of the present data, it may be concluded that the treatment window is probably very brief forpostischemic hypothermia to be effective in humans. A randomized and controlled experimentalstudy in a rat model by Markgraf et al. (95) showed significant reduction of neurological deficitsif 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 outcomeafter cardiac arrest if mild hypothermia is initiated within the 90 min treatment window. How-ever, experimental data also imply that delayed cooling can provide neuroprotection if the coolingperiod is long with gradual rewarming (97, 98).

The inconsistency in patient outcome in various clinical studies, particularly involving headtrauma, might be due to the delay of hypothermia initiation and possible other uncontrolledfactors. A paper by Clifton et al. (13) has been cited widely in the hypothermia community asevidence of ineffectiveness of hypothermia therapy for head trauma. However, as pointed outby Safar & Kochanek (27), the negative results for clinical trials on head-injured patients maybe 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 benefit ofhypothermia extends to only 90 min post trauma (21), and he is currently conducting a largeclinical trial to measure the effect. It is still a challenge to shorten the time between the injuryand induction of hypothermia. Usually, the process of transporting the patients to the hospitalis unproductive for this objective. A portable sensor attached to the patient to alert the medicalcenter of the impending case can minimize delay of treatment. Further, simple cooling approachesthat can be implemented by the Emergency Medical Service (EMS) personnel in the ambulancehave been suggested.

5.2. Cooling Extent

Because tissue temperature has profound effects on local metabolism and cellular activities, itis expected that different depths of hypothermia have varying effects on the clinical outcome ofminimizing secondary brain injury. Brain hypothermia can be categorized as deep/severe (<28◦C),moderate (28–32◦C), and mild (32–35◦C) (99). The traditional view that colder is better (100)has been questioned in the past decade (101). As brain temperature is decreased, greater systemictoxicity is observed, and the adverse effects outweigh the neuroprotection mechanisms associ-ated 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, deepcooling approaches are limited to facilities that have intensive care units and that medically justifythe collateral complications. Many animal studies suggest that the preferred cooling tempera-ture for neuroprotection is between 32 and 35◦C (94, 107). Many studies have shown improvedneurological outcome using mild hypothermia, compared with either the deep cooling group orthe normothermia group. Typically, these studies use whole-body cooling. One may conjecturewhether the associated systemic complications of hypothermia can be avoided if only the brain

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tissue is cooled and the rest of the body kept normothermic. In addition, when whole-body coolingis 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 andthe brain temperature, but large temperature variations may be created within the brain tissue ifcooling is applied to the head surface. Temperature gradients in the brain make control of thehypothermia state in a target tissue region a difficult task. More studies are needed to understandthe tolerance of brain tissue to local cooling.

5.3. Cooling Duration

Secondary effects of brain injury, including edema and elevated pressure, are known to persistseveral days after focal cerebral ischemia (108). Therefore, prolonging brain hypothermia ther-apy for an equivalent period may benefit those patients. Cooling for less than 1 h provided noneuroprotection in a rat model (92). Short periods of cooling may lead to transient rather thanpermanent neuroprotection. Experimental studies have tested whether a long cooling duration issafe for patients. Initially, 24 h were proposed, and later, the cooling duration was extended byBernard & 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 benefits observed inpatients with more than 48 h of hypothermia. Iwata et al. (109) note that the cooling extent andcooling duration may not be two independent factors in determining patient outcomes.

Although prolonged cooling may maximize clinical neurological benefits, it may also increasesystemic complications associated with cooling, especially in patients having compromised health.The optimal duration of treatment remains unknown for clinical application, especially whenother confounding factors are involved. Closely monitoring patients during hypothermia therapyshould be an important planning consideration.

5.4. Rewarming Rate

The importance of controlling the rewarming rate in the brain tissue from a state of hypothermiahas been widely documented. Rapid rewarming may result in a dangerous rebound of intracranialpressure elevation and cerebral perfusion pressure reduction; the importance of gradual rewarm-ing has been emphasized in multiple clinical studies (25). Previous theoretical analysis (110) ofsimulated passive (and uncontrolled) rewarming by removing the cooling device yields an averagecalculated rate of approximately 3◦C h−1. Recent animal experiments on rats (111) suggest that thefast 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 slowlyat 0.5◦C h−1. In some clinical trials, rewarming from hypothermia is conducted with a feedbackcontrol system over 18 h. It is critical to develop a thermoregulating system that allows not onlyfast 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 ofthe second law of thermodynamics. Unlike the heating process, which can be dissipative, coolingrequires 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 beproduced is directly proportional to the gradient that can be established across the medium and

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the thermal conductivity of the medium. Alternatively, convective blood flow can be used as theprimary 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 circulationin conjunction with conduction through the skin and cooling on the surface. A different optionfor cooling by convection is to introduce a chilled perfusate solution directly into the circulatorysystem, although this approach is highly invasive and has inherent risks. Both approaches havebeen adopted for inducing brain hypothermia, although heat removal by conduction through theoverlying tissue, including the skull, is of limited efficacy owing to the poor thermal conductivityof bone.

6.2. Whole-Body versus Selective Brain Cooling

Most of the clinical studies to date have examined only systemic (whole-body) hypothermia. Eitherthe whole body mass or the cardiac output is cooled using this approach. The major methodologicaldrawback of this approach is the inherently slow cooling rate (∼0.5◦ h−1) due to the large volumeof the human body to be cooled and the increase in thermal resistance due to arteriovenous shuntvasoconstriction (23, 39, 47). When extracorporeal blood cooling is applied, the cooling rate canbe greatly improved; however, the procedures are highly invasive and require extensive supportingequipment. With either approach, the major concern relating to whole-body cooling is that it mayproduce deleterious systemic effects such as metabolic, cardiovascular, pulmonary, coagulation, andimmunologic complications (23, 113). The increased risk of systemic complications when usingwhole-body hypothermia may outweigh the neuroprotective benefits of such therapy. Further,because of the long characteristic time of the human body, whole-body hypothermia may easilymiss 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 necessarybecause the human brain represents only 2% of body mass, and it receives 20% of resting cardiacoutput. Thus, blood circulating to the brain could be an effective transport medium if therewere 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 systemiccomplications (114) and maximize the protective benefits of hypothermia if it is initiated beforeor during the ischemic event. In this approach, the brain tissue is cooled directly or the bloodsupplied to the brain is cooled. The small mass of the head makes the cooling relatively fastcompared with whole-body cooling. The common carotid and vertebrate arteries are the majorblood vessels supplying blood to the brain and are somewhat accessible to cooling from theoverlying skin surface. Arterial blood temperature can be reduced via intravascular cooling, forwhich commercial devices are available, or through skin surface cooling, if an imposed temperaturegradient can adequately penetrate the tissue and reach the blood vessels. Conducting heat fromthe 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 temper-ature 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 al-cohol or ice water bathing. Surface cooling is an easy approach and does not require sophisticatedequipment. A clinical study by Mayer et al. (115) compared two surface cooling systems (Subzero

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and Arctic Sun) in controlling fever in neuro-critical-care patients and found positive outcomesin reducing fever burden in both systems. Arctic Sun–treated patients spent less time febrile, andthe cooling rate to achieve normothermia was faster than in the Subzero group. The side effectsincluded 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 witha flow 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 wasnot significantly different from the controls. Inducing mild whole-body hypothermia for 34 h inhead trauma patients with a coma score of 5–7 greatly improved the patients’ outcome (62% in thehypothermia group versus 38% in the control group) in a randomized, controlled clinical trial on87 severe head injury patients (23). A pilot study by Eicher et al. (116) on moderate whole-bodyhypothermia (33◦C) versus normothermia in excephalopathic neonates demonstrated favorableneurological outcomes.

In addition to introducing vasoconstriction and shivering, there are other drawbacks. Fullbody immersion makes it difficult to attach monitoring sensors to patients, and fast reductionof temperature is prevented by large body mass, thus elongating the time it takes to achieve thetarget temperature (117). Also, vasoconstriction induced by skin surface cooling greatly increasesthe thermal resistance of the skin, further hindering heat transfer from the body core to thesurface. It is reported that 3.5–11 h are needed to reach 33◦C using a cooling blanket (118). Inthe Copenhagen Stroke Study (43), it took more than 5 h to decrease the body temperature by2◦C; however, surface cooling may be more appropriate for children because they inherently havea smaller thermal mass than adults. Less than 1.5 h were required to achieve a body temperatureof 33.5◦C in newborn infants using a blanket precooled to 5◦C (45).

6.3.2. Blood cooling

6.3.2.1. Intravascular cooling catheter. Veno-venous extracorporeal blood cooling was proposedas a method to induce a fast cooling rate (119–125). This is a very attractive technique because itbypasses the thermal resistance of tissue and connects directly to the cardiac output. This methoduses a covered cooling catheter that is inserted into the femoral vein and advanced to the inferiorvena cava via abdominal X-ray guidance. The catheter is coated with antithrombotic coveringsto prevent clotting. Coolant is pumped to the catheter to achieve a fast heat removal from thevenous blood, with a cooling capacity of up to 150 W. In well-controlled studies using large andsmall animal models, the targeted brain temperature of 33◦C was reached within a reasonabletime frame after cooling initiation. The reported clinical trials have shown cooling rates varyingbetween 0.9 and 6.9◦C h−1, with hypothermia well tolerated by the patients. Some of the typicalcomplications associated with body surface cooling, such as infections, coagulopathy, and cerebraledema, 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 throughskin receptors. However, the surgical procedure involved is invasive, and vessel access time variesgreatly 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 hypothermiastate within a short time owing to its powerful cooling capacity (126–128). In well-controlledanimal 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 weightedimaging (DWI); however, the decrease was not significantly different from that in the controlgroup. Conflicting reports concerning the effect on brain function suggest that other uncontrolled

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factors may play a role. For example, in most clinical studies, the cooling was usually not initiateduntil several hours following the injury. The delays in cooling may diminish or even abrogatethe beneficial effects of hypothermia. This approach was also implemented to reduce the sizeof myocardial infarct in a pig model weighing from 60 to 80 kg (119, 129). Only 9% of the leftventricular myocardial area is at risk of infarct with hypothermia compared with the normothermiagroup (45%). Similar to other clinical trials for cardiac arrest, a recent clinical trial (126) foundshort-term favorable neuroprotection in the hypothermia group using an endovascular coolingapproach. A fast cooling rate (1.2◦C h−1), long cooling duration (24 h), and gradual and well-controlled rewarming rate (0.5◦C h−1) may be contributing factors that improved the survivalrate with favorable neurological outcomes and reduced patient mortality (127). Additional well-controlled and randomized clinical studies are still needed to demonstrate the safety and long-termefficacy of endovascular cooling.

6.3.2.2. Intravenous flushing. Chilled normal saline has been suggested as a preferred resus-citation fluid for patients with neurological and neurosurgical injuries. It is inexpensive, easy tostore, and frequently utilized as hydration fluid in hospitalized patients. This method of induc-ing hypothermia was tested in a swine model (129). For an extremely high intravenous infusionrate of 120 ml min−1, a core cooling rate was measured at up to 18◦C h−1. In a clinical study(130), ringer’s solution was infused at a rate of 100 ml min−1 to patients after resuscitation fromnontraumatic cardiac arrest, and no serious adverse hemodynamic complications occurred. Thisapproach is certainly very effective in achieving fast cooling. However, it is questionable whetherthe patients can tolerate such a large infusion rate. A theoretical analysis (131) was performedrecently to simulate the reduction of body temperature using this approach. Unlike the animalstudy during which the flow rate was very high, the simulation focused on a realistic and safe upperlimit of the infusion rate of either cold saline or 50% ice slurry saline mixture. The model identi-fied a cooling rate of 0.48 and 0.24◦C h−1 using 50% ice slurry and chilled saline, respectively, at450 ml h−1.

The use of cooled peripheral infusion is safe and likely without significant side effects if thepatients can tolerate the additional fluid. Inducing mild hypothermia in awake stroke patientsusing cooled intravenous fluid seems unlikely to cause discomfort. 30 ml kg−1 of Ringer’s solutionwas infused at a rate of 100 ml min−1 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 approximately3 h, it was possible to cool the body temperature from 36 to 34◦C using two liters of coldsaline at 4◦C (133). The observed cooling rate is similar to that predicted by the theoreticalmodel (131). In a recent case report by Bernard & Rosalion (134), a large volume of chilledsaline at 4◦C was injected intravenously during cardiopulmonary resuscitation, and the patientmade a satisfactory recovery. Lopez et al. (135) infused four to six liters of 3◦C lactate ringer at∼0.1 ml kg−1 min−1 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◦Cintravenous fluids at 40 ml kg−1 h−1, Frank et al. (136) demonstrated that the first signs of thermaldiscomfort occurred only when the body temperature reached 36◦C. Because of a lower shiveringthreshold, elderly may be susceptible to infusions of coolants when compared with the youngerpopulation. No cardiac abnormalities were observed during or after the cold fluid infusions (137).Based on mathematical modeling, peripheral infusions of saline in chilled or ice slurry form can beused as an adjuvant therapy to achieve mild hypothermia or to control fever. Intravenous coolantsadministered in an on-demand, temperature-guided, and supervised setting seem a reasonable

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approach for core cooling to avoid potentially unsafe use of extended fluid volumes and infusiontime periods.

6.4. Selective Brain Cooling

6.4.1. Head surface cooling. Head surface cooling via a helmet or an ice pack is practicable andeasy to apply, even in the prehospital setting. Saline perfusion to the subdural space has also beensuggested to cool the brain (138). Previous studies have indicated that it takes less than 1 h toestablish a steady-state temperature field after head surface cooling. This gives EMT personnelan advantage when cooling is initiated in the field to maximize neuroprotection of hypothermiatreatment. One clinical study evaluated the performance of a cooling helmet based on a NASAspin-off technology (114). In the hypothermia group of eight enrolled patients, brain temperaturedropped more than 1.8◦C within 1 h of the helmet application. Systemic cooling occurred onlyafter a prolonged cooling of more than 6 h. Minimal systemic complication was observed using thehelmet cooling. The clinical study (114) demonstrated that head surface cooling using a helmetis a relatively effective way to induce and maintain brain hypothermia while keeping the rest ofbody at normothermia.

An ice pack can more efficiently cool the brain tissue than a cooling helmet with the same coolanttemperature of 0◦C. Recent theoretical modeling showed the effects of a large thermal resistancebetween 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◦Ccoolant circulating inside. Improving the thermal contact between the coolant and scalp would, intheory, shorten the time required to achieve targeted cerebral hypothermia and improve coolingpenetration to the deep brain tissue. In the experiment performed in a cat model, 20◦C cold salinewas induced to the subdural space of the cerebral hemisphere by a catheter inserted into a parietalburr hole (138). The temperature was well tolerated by the subjects and effective in loweringthe brain temperature. It showed that hypothermia has enhanced the recovery of somatosensoryevoked 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 thecerebral cortex of the anterolateral temporal lobe of 18 patients (140). Chilled saline was infused tothe chamber. Temperatures lower than 25◦C were established in the cortex 6 mm below the surfaceof 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 adverseeffects were observed, although more rigorous clinical study is needed to evaluate the risks andbenefits of this hypothermia technique on patient neurological outcomes.

Head surface cooling relies on heat conduction from the scalp to the inner region of the brainhemisphere. Thus, because of the imposed radial temperature gradient, head surface coolingprovides more preferential cooling of the superficial areas of the brain than the deep regions. Thismethod of hypothermia induction can involve an interplay of conduction and convection effects.Large temperature gradients occur in the brain tissue, and temperature variation depends stronglyon the local blood perfusion rate. A temperature variation of more than 7◦C across the brain hasbeen reported (141). Theoretical simulations of temperature fields of head structures during headsurface cooling demonstrated similar trends as observed in the animal experiments. Cooling fromthe head surface has to overcome the thermal barrier of the scalp and skull as well as the largeblood perfusion rate in the brain tissue (110, 142). Significant cooling of the white matter is notfeasible unless the brain tissue is ischemic.

The beneficial effects of selective brain cooling using a cooling helmet are more evident ininfants owing to their smaller head size. A cooling cap filled with −30◦C solution was introduced

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to infant piglets after cardiac arrest and resuscitation (143). Brain temperature was reduced from37◦C to 31◦C within 1 h. Although the temperature of the coolant in the cap was below 0◦C, nonecrosis was observed. This implies that there was no freezing damage to the skin surface owing tothe thermal barrier of the cap material and the air gap between the cap and the skin. A recent clinicaltrial on infants with moderate to severe neonatal encephalopathy demonstrated favorable neuro-developmental outcomes in infants with less severe amplitude-integrated electroencephalogram(aEEG) changes after 72 h of selective head cooling using a cooling cap (144). Experimentalmeasurements of brain temperatures on newborn swine showed temperature reductions at allbrain sites (141).

6.4.2. Neck collar. Unlike head surface cooling, chilled neck collars aim to cool the arterialblood that supplies the brain tissue. There are several prototypes on the market. The feasibilityof this approach for inducing selective brain hypothermia has been evaluated theoretically byresearchers over the past 10 years. The major blood vessels in the neck region can be modeled asstraight tubes embedded in the neck cylinder. Theoretical simulation showed limited temperaturereductions (<1◦C) along the carotid arteries even when the neck surface temperature was reducedto 0◦C (145). The limitation on cooling predicted in this study is largely due to the deep locationsof the carotid arteries. Temperature reduction along the arteries depends on not only the lengthof the cooling collar but also on the blood flow rate of the arteries. This model was later modifiedto include the vertebral arteries owing to their relatively superficial locations and their smallblood flow rates (146). Depending on the cooling collar temperature, up to 37 W of heat couldbe removed from the arterial and venous blood in the neck region. Although the theoreticalanalysis failed to demonstrate significant 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 asmuch as 0.69◦C h−1 by cooling blood flow through the superficial jugular vein. Therefore, theneck collar’s small size and portable nature may make it suitable to provide an initial downwardtrend 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 surfaceand an embedded blood vessel is the major thermal barrier for effective removal of heat from thearterial blood, an interstitial cooling device was proposed to bypass the barrier. Wang & Zhu(147) first proposed inserting a cooling device into the neck muscle to ensure close physicalcontact with the arterial blood, thereby enhancing the contact surface area. The advantages of thisapproach include the small size of the thermal source device, its powerful cooling capacity, fastcooling capability, and adjustable rewarming rate. The physical principle of the cooling approachwas demonstrated by the theoretical simulations of the neck and head temperature fields. Thesimulations predicated a reduction in the temperature of the common carotid arterial blood byat least 2◦C within 30 min. A prototype of the device was tested independently in a rat model bytwo 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 deviceproduces a nearly uniform temperature field in the rat brain tissue because the chilled arterialblood 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 braintemperature 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 than70% (149). Both experimental studies demonstrated the feasibility and efficacy of this approachin small animal models. Large animal models are needed to evaluate the safety and effectivenessof the technique.

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6.4.4. Intracarotid flushing. Because most of the noninvasive cooling methods are not effectivein reducing the brain temperature quickly, more aggressive techniques have been suggested. Byadapting the approach of veno-venous blood cooling, researchers have proposed selective coolingof only the blood supply to the brain. Because cold saline infusion is able to produce a relativelyfast cooling rate in the whole body, infusing cold saline via a catheter inserted into the femoralvessels and advanced to the carotid artery should have considerable potential for achieving rapidbrain cooling. Several theoretical studies were performed to evaluate the clinical feasibility of thisapproach. On the basis of a three-dimensional (3D) mathematical model developed by Neimarket al. (150), it was shown that an infusion flow rate of 30 ml min−1 is sufficient to induce moderatebrain cooling within 10 min in the brain, after which hypothermia can be maintained. A fast coolingrate (4◦C 10 min−1) was observed when 6 ml cold saline was infused to the middle cerebral arteryin a rat model (151). In this study, brain cooling significantly improved the motor behavior of thetested rats; however, reduction in the infarct volume was not substantial. Because a rat brain ismuch smaller than a human brain, the cooling extent and rate for the rat experiments may notbe applied directly to the humans. Although the theoretical models have provided proof of theprinciple, future experimental study on large animals and clinical trials are needed to examine thefeasibility of this technique.

6.4.5. Intraparenchymal cooling. Given that thermal conduction resistance between the skinand 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 patentby neurosurgeons and researchers at the University of Chicago and Argonne National Laboratorydescribes such a cooling probe. The cooling device consists of a 2.5 cm long, dual-lumen stainlesssteel shaft with cold water circulating from a slurry ice bath to the device. The diameter of thedevice is approximately <2.7 mm.

A recently published paper (152) analyzes the temperature distribution in the brain tissuesurrounding the intraparenchymal cooling device. The temperature of the device surface can belowered to 6◦C with a circulating ice-slurry solution. The theoretical simulation illustrated howthe cooling field penetrates into the brain tissue. One important factor is the local blood perfusionrate, which is well known to be as high as 0.0133 s−1. The effect of blood perfusion will limitthe zone of influence of the cooling device, because the cooled blood is rapidly redistributedand diluted throughout the entire blood circulation. In contrast, in clinical settings where brainperfusion is either not present at all (e.g., the ischemic core within a brain infarction) or markedlyreduced (e.g., penumbra region around an ischemic brain core), both the blood perfusion rateand the temperature will have a reduced counteracting influence on the probe, thus allowing thecooling zone to extend further laterally from the device when compared with the cooling of anoninjured brain. Depending on the extent of blood perfusion, cooling penetration achieved bythe 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. Finalsteady 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 istoo invasively aggressive to be applied in many therapeutic scenarios. The inventor argues thatthe device can be used side by side with other routine neuro-critical-care procedures, includinginsertion of both rigid and flexible catheters to drain ventricular fluid, as well as the use of probesto monitor cerebral pressures. If these catheters are inserted via a small hole drilled in the skull, it isconceivable that modifications of those catheters to include the cooling device can be implementedwith no added risk or complication.

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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 andsafe devices to achieve target cooling rates and temperatures. New technologies are typically eval-uated for thermal efficacy and safety in small and large animal models to determine their suitabilityfor testing in humans. During the design, patient safety is a prime consideration, including issuessuch as leakage of coolant, induced freezing damage to tissue, physical trauma, etc. Sterilizability,size minimization consistent with thermal performance requirements, and physical packaging aretypical design considerations during the development of the device.

In general, there are two categories of device designs that are used clinically for therapeutic hy-pothermia: skin surface and endovascular cooling. More than six companies (Medivance, MTRE,Seabrook, Cincinnati SubZero, Birchbrook, and Garnar) manufacture surface cooling devices suchas cooling blankets, garments, helmets, and pads. This category of devices is based on noninvasivemethods and, to date, has been most broadly applied in clinical trials. An alternative approach ispresented by AVACore in which an applied negative pressure to glabrous skin in conjunction withcooling is used to enhance blood perfusion through arteriovenous anastomoses, thereby increasingconvective energy transport with the body core. This technique has the potential for providingmuch faster cooling rates. There are three companies (Radiant Medical, Innercool Therapies, andAlsius) that have developed endovascular catheters for cooling human blood as it flows past thedevice when inserted into a large vessel. Endovascular cooling is superior in providing a fast cool-ing rate; however, its major drawbacks are blood clogging and clotting, invasive surgical insertionprocedures, and complications associated with whole-body cooling. Other approaches, such asintracarotid cooling and interstitial cooling in the neck, are in their infant stage and are yet to betested 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 temper-ature during hypothermia. Even a small reduction in brain temperature can improve neurologicaloutcomes of patients suffering brain injury. Temperature variation within normothermic braintissue is usually very small; however, especially during therapeutic hypothermia, temperature gra-dients can develop not only between brain and core but also within regions of the brain (38, 53,118, 153–155). Information on internal temperature gradients is difficult to obtain clinically bymeasurement 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. There-fore, analytical methods for understanding the transient and spatial temperature distribution inbrain tissue during hypothermia therapy are clinically valuable.

Quantitative thermal modeling aids in identification of an optimal treatment protocol, and withappropriate constitutive input data, affords the opportunity for designing personalized therapeuticregimens. Theoretical modeling provides clinicians with powerful tools to improve the ability todeliver safe and effective therapy. Most importantly, thermal modeling permits the identificationand 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 Pennesbioheat equation (156) that simplifies the thermal contribution of local blood vessels as a simpleheat source term added to the traditional heat conduction equation (110, 142, 147, 150, 152,

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157–161). With the advancement in computational resources, researchers have the capability tosimulate the 3D temperature field of the head and neck and to consider multiple large blood vesselsindividually in the model. When point-to-point temperature nonuniformities are important, amodel that incorporates perfusion through the vasculature is necessary to predict accurately thetissue temperature field; however, because of the complex vascular geometry, one may model onlyselected large blood vessels individually and neglect the others. There were several attempts inthe past to model large blood vessels, including the carotid arteries and jugular veins in the neck,during brain hypothermia (145–147, 162). In those studies, temperature decay along the largearteries was used to evaluate whether various techniques could induce sufficient cooling to thearterial blood supplied to the brain. Owing to the complicated vascular structure, it is difficult tomodel effects of individual blood vessels in the brain region. Van Leeuwen et al. (163) predictedtemperature contours based on a detailed vasculature in the brain and found that they agree verywell with those predicted by the Pennes model. This may be mainly due to the large rate and diffusepattern of blood perfusion in the brain tissue, for which the Pennes bioheat equation is a preferredapproach. Advanced computational methods also allow researchers to model the head with a morerealistic geometry than a simple hemisphere structure. The head geometry is usually based onmagnetic resonance images (MRIs), which can be imported into grid-generating algorithms andthen 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 thosepredicted by a simple, layered head geometry.

One of the major challenges in mathematic simulation of cooling and rewarming processesis assessment of local blood perfusion variations in response to cooling. In most theoretical sim-ulations, blood perfusion is usually considered a constant during cooling or is considered to bedecreasing as a function of the local tissue temperature following the Q10 law (164, 165). Thepredicted temperature distribution in the brain is in agreement with the observed temperaturefield during steady state; however, there is a large discrepancy between theory and experiment onhow 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, thermocou-ples were inserted into the brain to monitor the temperature reduction and recovery (111). Themeasured 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 flow rate is unchanged during the simulation.These results imply that the change of the blood perfusion rate in tissue contributes significantlyto 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, andlog CMRO2 (the cerebral metabolic rate of oxygen consumption). A mathematical expression ofthis relationship is given by

CMRO2 = CMRO2,n · QTt −37

1010 , (1)

where CMRO2,n is the normal cerebral metabolic rate of oxygen consumption, and Q10 is a constantfactor, which has been reported (165) to vary between 2 and 4.4 based on correlations withexperimental 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 calculatedthat hypothermia decreases cerebral metabolic rate by an average value of 7% for the first 1◦Creduction in temperature, whereas metabolic rate is reduced to one-half of the normal valuewhen the temperature reduction is 10◦C. This type of relation is analogous to the Arrheniusequation. During normal conditions, cerebral blood flow (CBF) may follow the same pattern

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as that of cerebral metabolism owing to their direct coupling. Several temperature simulationshave incorporated the Q10 law (110, 152, 157, 158). Because the local blood perfusion keepsdecreasing with the temperature during cooling, the temperature field from the cold surface canpenetrate more readily into the deep brain region, which, in turn, would further trigger perfusionreduction. If the temperature dependence of perfusion progresses during cooling, the result wouldbe an extended time to reach a steady state.

During cerebral ischemia or head injury, not only may the Q10 value change but also CBFmay be decoupled from metabolism. A number of studies have examined the variation of CBFduring systemic hypothermia. Using the radioactive microsphere technique, Busija & Leffler (166)measured CBF in anesthetized newborn pigs. They concluded that systemic hypothermia reducedCBF secondarily to the depression of cerebral metabolic rate. Verhaegen et al. (167) measured thecortical blood flow in anesthetized rats using a laser Doppler flowmeter (LDF) and found that CBFwas reduced during moderate hypothermia. Okubo et al. (168) examined the effect of systemiccooling on cerebral metabolism and regional CBF variation in newborn piglets. They measuredthe regional CBF with colored microspheres and demonstrated that a reduction of cerebral cortextemperature resulted in a decrease in the blood flow in all brain regions. Unlike many experimentalstudies on CBF response during systemic cooling, there have been only a few studies on the effectof 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 whole-body cooling and illustrated that the global CBF was reduced during both whole-body coolingand selective brain cooling. Ibayashi et al. (169) demonstrated that the regional CBF decreasedwhen selective brain cooling was implemented on rats. However, a previous study (170) using theLDF technique showed that the cortical CBF in normal lightly anesthetized rats increased duringselective brain cooling.

LDF has been used to monitor blood perfusion in superficial areas of the brain. To measurethe blood perfusion rate of brain tissue, the LDF probe must be inserted into the brain to haveaccess to the measured region because its sensing signal cannot penetrate the skull. Another lim-itation of LDF is that it may not be suitable for measuring global blood flow changes in thebrain. Microspheres of a selected diameter, a standard and popular technique for measuring lo-cal blood perfusion rate in tissue, are injected into blood and allowed to circulate freely untilthey become lodged in the smaller capillaries. It is possible to determine the blood perfusion atdifferent times using different colored and sized microspheres introduced serially into the circu-lation. 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 mod-els. More recently, MRI has been used to detect the cerebral perfusion in animal models duringbrain hypothermia (16). Because of the relatively long acquisition time for a 3D MRI scan, thetechnique may not be suitable for studying the response of blood perfusion during cooling. Ithas also been proposed that the variation of the blood flow rate of the common carotid arteryshould be considered as an index of the global CBF and how it changes during brain hypother-mia should also be considered (111). It is estimated that more than 80% of the blood suppliedto the brain is from the common carotid arteries. The blood flow rate of the common carotidartery can be measured continuously using an LDF applied in an in vivo setting to study thetransient behavior of temperature and blood flow responses during selective brain cooling andrewarming (111). Very similar transient profiles of the brain temperature and blood flow rateof the common carotid artery as characterized by their characteristic time constants were ob-served in rats (111). Nonetheless, more rigorous experimental verification is needed to establishthe correlation between the CBF and blood flow rate of the common carotid artery. The ac-curacy of theoretical simulations is still questionable unless the simulations can be verified with

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experimental data that continuously monitor the local blood perfusion rate during cooling andrewarming.

8. OPPORTUNITIES FOR BIOMEDICALENGINEERING CONTRIBUTIONS

As the mechanistic basis of the therapeutic application of hypothermia for ischemic brain injuryimproves and becomes more complete, it may become possible to accurately and predictably designtreatment protocols to achieve specific outcomes. For example, there is an accumulating body ofevidence that points to the need for a rapid reduction in brain temperature following a traumaevent in order to realize the potential benefit of hypothermia therapy. The minimum temperaturedrop is thought to be at least 2◦C, and the window of opportunity in which it can be effective islimited to 90 min or less. Quick initiation of rapid cooling is apparently an essential feature ofhypothermic therapy. The practical implementation of rapid brain cooling would benefit greatlyfrom a cooling process that could be started in the field by first responders for whom specializedtraining and skilled procedure requirements are minimal. Further, the requirement for coolingthe brain at a rate of 1.5◦C h−1 or higher imposes limitations on the types of technology thatcan be used for removing heat rapidly from the interior of the body. The combined criteria ofsimple, safe, and fast cooling define the considerations facing biomedical engineers in designingnew devices and procedures.

Recent advances by thermal physiologists have opened an opportunity for achieving the rapidcooling of the body thermal core (79, 91, 172, 173). Their technology uses an applied negativepressure on glabrous skin to mechanically distend arteriovenous anastomoses, thereby greatlyincreasing the cutaneous blood perfusion. By diverting a significant fraction of the cardiac outputto the skin, where there can be an effective heat transfer with the environment, it is possible touse the circulatory system as a convective conduit for thermal energy between the body surfaceand the thermal core, including the brain. In initial studies with humans, it has been possible toachieve rates of change of core temperature of 10◦C h−1 and higher, which would be adequate forhypothermia induction in cases of TBI. One concern raised by neurosurgeons is decrease in bloodpressure, which can be dangerous to patients with compromised health. Although this technologymay not be suitable for clinical applications in hypothermia, it illustrates that there are possibilitiesfor extending the currently limited performance range of technologies into the domain in whichmethods of hypothermia therapy could be made available for widespread adoption.

SUMMARY POINTS

1. Hypothermia has a documented efficacy 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 benefit is not definedclearly, although there are indications that it may as little as 2◦C to a brain temperatureof 35◦C.

3. Clinical evidence is accumulating that shows time is of the essence for implementinghypothermia in the target tissue. The window of opportunity appears to be 90 min orless. 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 benefit,it is important to avoid rapid rewarming from hypothermia.

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FUTURE ISSUES

1. The therapeutic mechanism of action of hypothermia is not well understood, and there-fore the ability to design treatment protocols for optimal efficacy is compromised. Al-though the problem is quite challenging, it presents a major opportunity for significantcontributions.

2. Effective cooling of the brain remains a major difficulty in the practical use of hypother-mia. Engineering methodologies should play a key role in identifying new and effectivetechnologies and devices and adapting them for clinical application.

3. It is widely held that treatment of brain ischemia requires a quick reduction in temperatureof the affected tissue to a state of mild hypothermia, possibly within an hour of theprecipitating event, in order to achieve full neuroprotective benefit. New methods anddevices are needed to quickly and safely produce mild hypothermia of the brain byminimally skilled personnel in a field environment.

DISCLOSURE STATEMENT

The authors are not aware of any biases that might be perceived as affecting the objectivity of thisreview.

ACKNOWLEDGMENTS

Preparation of this review was supported in part by the Robert M. and Prudie Leibrock EndowedProfessorship in Engineering at the University of Texas at Austin and the State of MarylandTEDCO fund.

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RELATED REVIEWS

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AR382-FM ARI 26 May 2009 14:3

Annual Review ofBiomedicalEngineering

Volume 11, 2009Contents

Implanted Neural Interfaces: Biochallenges and Engineered SolutionsWarren M. Grill, Sharon E. Norman, and Ravi V. Bellamkonda � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Fluorescent Probes for Live-Cell RNA DetectionGang Bao, Won Jong Rhee, and Andrew Tsourkas � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �25

Proteomics by Mass Spectrometry: Approaches, Advances,and ApplicationsJohn R. Yates, Cristian I. Ruse, and Aleksey Nakorchevsky � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �49

The Influence of Muscle Physiology and Advanced Technologyon Sports PerformanceRichard R. Neptune, Craig P. McGowan, and John M. Fiandt � � � � � � � � � � � � � � � � � � � � � � � � � � � �81

Patient-Specific Modeling of Cardiovascular MechanicsC.A. Taylor and C.A. Figueroa � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 109

Hypothermia Therapy for Brain InjuryKenneth R. Diller and Liang Zhu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 135

On the Biomechanics of Vaginal Birth and Common SequelaeJames A. Ashton-Miller and John O.L. DeLancey � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 163

Cancer Cells in Transit: The Vascular Interactions of Tumor CellsKonstantinos Konstantopoulos and Susan N. Thomas � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 177

Microengineered Platforms for Cell MechanobiologyDeok-Ho Kim, Pak Kin Wong, Jungyul Park, Andre Levchenko, and Yu Sun � � � � � � � � � � 203

Living-Cell MicroarraysMartin L. Yarmush and Kevin R. King � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 235

Cell Mechanics: Dissecting the Physical Responses of Cells to ForceBrenton D. Hoffman and John C. Crocker � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 259

Bioengineering Challenges for Heart Valve Tissue EngineeringMichael S. Sacks, Frederick J. Schoen, and John E. Mayer, Jr. � � � � � � � � � � � � � � � � � � � � � � � � � � 289

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l use

onl

y.