Chapter 15 / Therapeutic Hypothermia

15

253

Therapeutic Hypothermia
in the Treatment of Cardiac Arrest
Benjamin S. Abella, MD, MPhil,
Terry L. Vanden Hoek, MD,
and Lance B. Becker, MD, FAHA
CONTENTS
INTRODUCTION
HISTORY OF INDUCED HYPOTHERMIA
INTRA-ARREST VS POSTARREST HYPOTHERMIA
DEPTH OF HYPOTHERMIA
PHARMACOLOGICAL AUGMENTATION OF HYPOTHERMIA
MECHANISMS OF HYPOTHERMIC PROTECTION
METHODS FOR SUSPENDED METABOLISM AND PROTECTION
FROM ISCHEMIA WITH AND WITHOUT HYPOTHERMIA
METHODS OF HYPOTHERMIA INDUCTION
FUTURE OF HYPOTHERMIA AND SUSPENDED ANIMATION
REFERENCES

Cold acts on the living parts by blunting the sensibility of those organs . . . the parts may
remain for a longer or shorter period in state of asphyxia without losing their life; and
if the cold be removed by degrees . . . the equilibrium may be easily reestablished with
the function of the organs. . . .
—D.J. Baron Larrey, 1814 (1)

INTRODUCTION
Sudden cardiac death remains a major medical challenge despite the advent of defibrillation decades ago. There are few minutes to defibrillate the heart and thereby stop
ongoing ischemic injury to key organs such as the heart and brain, and few therapies
proven to protect against the postresuscitation phase of cardiac arrest (CA)—when up to
90% of patients go on to die despite successful defibrillation (2). New approaches are
desperately needed to improve CA survival, and the induction of transient hypothermia
may be one of the most promising of new approaches (2). Hypothermia used to protect
against conditions of low blood flow has historically been induced at different times
From: Contemporary Cardiology: Cardiopulmonary Resuscitation
Edited by: J. P. Ornato and M. A. Peberdy © Humana Press Inc., Totowa, NJ

253

With these studies. induced by applying cooling blankets in the subset of CA patients having return of spontaneous circulation (ROSC) who remained unresponsive (3. coagulopathies. There are many unresolved questions regarding the use of hypothermia in CA treatment. Few studies have determined the optimal depth of intra-arrest cooling. 1. The goal of this hypothermia was to prevent neurologic injury although maintaining a temperature warm enough to prevent the cardiac and numerous other side effects of more profound cooling (e.4). The optimal depth of hypothermia is much lower in the pre-arrest setting than after return of spontaneous circulation (ROSC). 1): pre-arrest. hypothermia has moved from the laboratory to active clinical use. Intra-arrest cooling. two seminal papers were published describing the use of hypothermia to successfully treat resuscitated CA patients (3.4).. infections). these are most often used as adjuncts to the use of hypothermia. “Suspended animation.. hypothermia can have adverse effects. relative to the arrest (see Fig. suspended animation) long enough for more definitive circulation (e. metabolic correction. The most widely studied method to induce suspended animation has been induced hypothermia. cardiac bypass) to be established and life restored. Timing of hypothermia induction relative to circulatory arrest. intra-arrest. and postarrest. which may include cardiopulmonary bypass (CPB).e. due in large part to the technical difficulties involved in inducing profound hypothermia during the low-flow states of sudden CA. Little is known about the optimal depth or clinical potential of such hypothermia. the patient is stabilized. is a process that allows “rapid preservation of viability of the organisms in temporarily unresuscitable CA. First.” as defined by Safar et al. and reanimation is initiated. Pre-arrest cooling is typically induced to as low as 20°C for cardiac surgery and is induced before and simultaneous to the time of arrest. Although many methodologies have been studied under the rubric of suspended animation. hopefully to survival without brain damage” (5). Certainly. reduced .. cardiac arrhythmias. With advance medical interventions. when cooling is induced after failed initial CPR.254 Cardiopulmonary Resuscitation Fig. which allows time for transport and repair during clinical death and is followed by delayed resuscitation. rewarmed. Recently.. In this paradigm. Postarrest cooling to 32 to 33oC was found to be protective in recent human CA trials. the optimal degree of hypothermia has yet to be established. including CPB and pharmacologic interventions (6). has the potential to induce a stasis state for a period of time (i.g. victims of CA may be cooled to some target temperature and maintained at this temperature for a specific period of time. and controlled reperfusion.g. This cooling was protective despite taking 8 hours to reach target temperature after ROSC (4). including coagulation derangements.

4). which have developed our understanding of its use. or cooling some time before CA.Chapter 15 / Therapeutic Hypothermia 255 immune system function.7). Hypothermic protection was also noted by Napoleon’s chief battlefield surgeon. Clinical studies to date have all maintained mild hypothermic conditions at least 12 hours (3. Finally. we will define hypothermia as either mild (34–36oC). Certainly. is what duration of hypothermia is required for protection. including minimizing the logistical difficulties of maintaining a constant cooled state.4. depressed pulmonary function. Recent large-scale clinical trials have demonstrated significant benefit from induced postresuscitation hypothermia (3. show that even 1 hour of moderate hypothermia can confer a significant survival benefit after CA (21). Some animal data. a number of other aspects of hypothermic suspended animation remain to be examined. suggests that earlier induction of hypothermia confers a greater benefit (18.19). is only possible in the setting of anticipated surgery. either to provide additional benefit or protect against certain adverse effects of a cooled state? This chapter addresses elements of the history of hypothermia. Unpublished data from our laboratory. He observed improved survival of injured soldiers . However. For convenience of discussion in this review. 14 and 15). important physiology aspects to hypothermia. the therapeutic window of hypothermia must be defined to provide maximum benefit. Prearrest hypothermia. Another question. cooling to target temperatures may take several hours (16. who advocated packing bleeding patients in snow (22). or cooling during cardiopulmonary resuscitation (CPR). Deep hypothermia has largely been confined to studies of specific applications such as brain cooling during surgery and reduced cerebral perfusion (12). and other possible alterations (7–10). using a mouse model of CA. There are three general time periods in which hypothermia may be considered. which remains unresolved. a shorter duration of cooling would have a number of clinical advantages. Finally. animal studies have shown benefit from hypothermia lasting only 2 to 6 hours (19. the laboratory data. during the invasion of Russia. This question has not been directly addressed in clinical studies at this time. These studies raise a secondary timing question related to postresuscitation hypothermia: is the delay in hypothermia initiation clinically important? In the clinical arena. although only two are realistic for clinicians. or cooling after ROSC. The mechanisms by which hypothermia may protect ischemic and reperfused tissues will be introduced. Most clinical research has concentrated on the use of mild or moderate hypothermia. after an evaluation of the various techniques used to rapidly cool patients. has been the most commonly attempted timing strategy and is certainly the most clinically convenient. the future of hypothermia as therapy for sudden death will be discussed. The timing of hypothermia is another crucial question.17). Some animal investigations have directly compared different depths of cooling (13).20). HISTORY OF INDUCED HYPOTHERMIA The protective effect of hypothermia induction for resuscitation has been suggested since the time of Hippocrates. How quickly should patients be rewarmed at the end of a period of hypothermia? Would certain drugs serve as useful adjuncts to hypothermia. Intra-arrest hypothermia. when arrest is iatrogenic and controlled (reviewed in refs. Therefore. is theoretically attractive and a promising area of current research but has not been attempted clinically. detailed in this chapter. or deep (15–28oC [11]). moderate (28–34oC). and also minimizing the potential adverse effects from hypothermia. Baron Larrey. Postresuscitation hypothermia.

both ischemic and nonischemic in nature (24–26). the first reported use of induced hypothermia was in the setting of malignancy. status epilepticus (30). Given the animal data on exsanguination and cooling. it was considered well tolerated (34). Others have suggested that more dramatic therapies were developed that overshadowed cooling as a possible therapy. 12 patients were cooled with a survival rate of 50%.g. and CA (5. For example.256 Cardiopulmonary Resuscitation left in the snow compared to those treated with warm blankets and heated drinks (1. and the ischemic illnesses of myocardial infarction (MI).39). with the goal of cerebral protection (35). and whole animal models in which arterial supply to the organ in question is temporarily occluded (19. Both of these early CA studies used moderate hypothermia of 30 to 34oC in patients after resuscitation from CA. In 1939. A decade later. Interestingly. burns (31).44). stroke. compared to 14% survival in 7 normothermic control patients (36). arrhythmia (32). A variety of ischemia-reperfusion (IR) model systems have been developed over the last two decades. These include traumatic brain injury (27–29). which may have dampened enthusiasms (38. It was understood from military combat experience that definitive therapy for penetrating trauma was often delayed for practical reasons (e..23). in an isolated rat liver IR model. Additionally.26). the field of induced hypothermia lay relatively dormant. It was during this period of time that the term “suspended animation” was introduced. Induced hypothermia has been studied in a wide variety of illnesses. Studies of hypothermia in both CA and IR models are discussed here. when it was demonstrated in a ventricular fibrillation (VF) dog model of CA that mild-to-moderate hypothermia could be induced to improve outcomes (41. all who were cooled and survived arrest (37). isolated organ (48). suspended animation). including cellular (47).g. such as controlled ventilation. adverse effects of hypothermia were described. During the 1960s and the 1970s.42). In this latter category are included experiences with human IR. it might well fall into unwarranted disrepute before the facts and fallacies accompanying it were clearly defined” (40). animal stroke or MI models). One scientist from the early days of induced hypothermia correctly summarized the ensuing skepticism toward hypothermia when he stated: “If a hazardous procedure such as this were mishandled. One of these pioneering papers presented a series of four patients. Although hypothermia to 32oC for 24 hours did not prove effective for the stated goals. and that measures were needed to preserve exsanguinating soldiers until appropriate care could be delivered (45. much of the work pertaining to hypothermia and ischemic disease has focused on focal ischemia and reperfusion (e. after reperfusion). in the context of an exsanguination CA dog model (43. INTRA-ARREST VS POSTARREST HYPOTHERMIA Most studies of induced hypothermia have involved cooling after resuscitation (or. Since these initial observations in the 1980s and early 1990s.20). for reasons that remain unclear. Two other studies using hypothermia as therapy for CA were also published (36). Fay and colleagues (34) treated patients with metastatic carcinoma. sepsis (33).. and CPR (24). in the IR paradigm. Interest in “resuscitative hypothermia” was rekindled by Safar and others at the University of Pittsburgh.. . with the goal of both pain reduction and retardation of tumor growth.e. it appeared that hypothermia might be a suitable approach (46). Bigelow studied the induction of hypothermia in the setting of cardiac surgery. transportation and access to surgical care). In the other study. i. monitored intensive care unit management. for example during coronary vascular procedures (49).

A number of canine studies have also demonstrated benefit from postresuscitation hypothermia. but what data does exist suggests that this strategy of cooling also provides significant benefit in IR injury. and neurologic damage was minimized on histological examination (56). which can only be studied easily in whole animal models. Additionally. In a reversible global cerebral ischemia model using gerbils. They found that hypothermia to 32 to 33°C applied immediately after the onset of ischemia provided greater protection from infarct than equal hypothermia applied just 45 minutes later. Postresuscitation hypothermia has been attempted in a number of CA models as well. which suggests that even a delay in cooling within the ischemic period can lead to poorer outcomes. there is both decreased liver inflammation and cell death as well as reduced pulmonary injury. even though the lungs were not rendered ischemic or cooled (52). A comparison of intra-ischemic vs postischemic cooling was tested in a peripheral nerve IR model. produced IR injury via bilateral carotid occlusion in the gerbil. performance scores after recovery were greatly improved compared to normothermic controls. (20) compared a variety of hypothermia strategies. In a rat asphyxia model with 8 minutes of CA. in their study. There have been fewer studies of intra-arrest (or intra-ischemic) hypothermia. Canevari et al. either at normothermia or at 30oC. Markanian et al. including early vs delayed cooling. and therefore the authors provide a possible link between hypothermia and prevention of reperfusion injury. although damage becomes most apparent in the reperfusion period. using a rat asphyxia model of CA (59). Patel et al. This result was statistically significant at 4 weeks after the experiment. focal hypothermia may protect other organs via its effects on humoral issues. which was then reversed and allowed to reperfuse for 2 hours. used a rabbit rectus femoris muscle IR model and showed that intra-ischemic hypothermia during ischemia increased muscle viability significantly (57). the underlying injury mechanism may begin during ischemia.Chapter 15 / Therapeutic Hypothermia 257 reactive oxygen species (ROS) production was diminished by maintaining liver tissue at 34oC after reperfusion (50). improved neurologic deficit scores. suggesting a lasting benefit (54). In another example of whole animal investigation. Similarly. dogs that were cooled to 33oC and maintained for 24 hours with extracorporeal lung and heart assist had better survival. the normothermic animals had significantly impaired mitochondrial complex IV activity compared to the animals treated with hypothermia (53). A clear comparison of different cooling timing strategies was performed by Xiao et al. and intra-ischemic cooling to 28oC showed superior benefit in a variety of parameters including electrophysiological and histological endpoints (58). Thus. Two studies in focal tissue ischemic models are illustrative. and decreased heart necrosis compared to normothermic animals (55). Interestingly. hypothermia to 34oC and induced hypertension for 60 minutes immediately after ROSC produced improved survival compared to normothermic animals. The investigators found that cooling animals to 34oC before arrest provided much better protection from injury than similar hypothermia induced during resuscitation. to direct protection. cerebral ischemia was induced for 3 hours. . After 15 minutes of VF. After this time. in dogs maintained on CPB at 34oC after 20 minutes of an exsanguination CA model. Wilson et al. This provides an important example of dissemination of pro-injury issues from a site of IR. found that when rat liver is exposed to IR and then focally cooled to 25oC. It is widely felt that ROS contribute to reperfusion injury and tissue damage after resuscitation (51).

performed cooling in a canine exsanguination model of CA. A drug–hypothermia combination was tested in an isolated lung IR model. hibernation induction agents. and deep hypothermia (15–28oC). Matsumoto et al. demonstrating that moderate hypothermia may confer more protection than mild hypothermia. mild hypothermia was better and colder temperatures possibly harmful (13.3oC (60). glutamate receptor blocking agents.62). with regards to histological and functional outcome measures. however. mean starting temperatures were 37. Antioxidants have been shown in many model systems to mini- . anticoagulants. Laptook et al. In a direct comparison of hypothermia with a pharmacologic treatment for IR injury. and even thrombolytics. Even 1oC of core brain cooling in the intra-arrest setting following normothermic arrest has been shown to improve outcome. Certain of these agents may work by the induction of hypothermia (65). Similarly. either by themselves or in conjunction with other measures (reviewed in refs. Similarly. moderate (28–34oC). As described in the introduction to this chapter. There are other agents that might also confer improved survival when combined with hypothermia treatment. other investigations in dog exsanguination CA also found benefit of 34oC target temperature compared to 36oC (56).5oC of cooling. Indeed. better performance and histologic scores were obtained if animals were cooled to 33 to 34oC rather than 36oC (61). and it was found that hypothermia to several depths in combination with prostaglandin E1 showed improved protection from injury than either agent alone (70). function was improved when a b-opioid agonist pentazocine was used in combination with hypothermia at 34oC (71). In a piglet model of brain ischemia. so 36oC did represent an average 1. found a clinical benefit from just 1 hour of postreperfusion hypothermia to 35. when cooling is induced after the return of blood flow following CA. no direct comparisons have been made regarding different depths of cooling and patient outcomes. These agents have included free radical scavenging molecules. In human trials to date. in some animal models. there is a somewhat arbitrary convention grouping depth of cooling into several categories: mild (34–36oC).5oC. Possible explanations include decreased microcirculation flow (28). They found that hypothermia to 35oC was more protective than the barbiturate. Deeper levels may be protective in the intra-arrest setting.258 Cardiopulmonary Resuscitation DEPTH OF HYPOTHERMIA Another crucial parameter of hypothermia is the depth to which cooling is applied. which induces a mild hypothermia (66). One example of this is the selective _-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX. They found that when cooling was performed for 12 hours after arrest. The authors did not test the two modalities in combination to see if further improvement could be generated. Whether this logic can be extended to deeper levels of hypothermia remains an important question. the optimal temperature for greatest protection in this setting remains unknown (42). Other drugs are thought to be helpful after ischemic insult by reduction of metabolic demands (67.8oC compared to “normothermic” control animals at 38. 63 and 64). and several studies have actually compared different temperatures in the same model. Note than in their animals. although after the heart is defibrillated and circulation reestablished more mild levels are likely best. compared thiopental burst suppression dosing vs hypothermia in a rabbit model of spinal cord IR (69). Woods et al.68). found that in isolated rabbit hearts. CA and IR experiments have focused primarily on mild and moderate hypothermia. PHARMACOLOGICAL AUGMENTATION OF HYPOTHERMIA A variety of drugs have also been considered in strategies for suspended animation or ischemic protection. Schwartz et al.

Similarly. In a rat brain ischemia model. Thus.80). and that different mechanisms may protect in different tissues or at different times during ischemia or after reperfusion (24. Other investigators have shown that mild hypothermia in rats improves postischemic cerebral blood flow disturbances (82). Another marker of general physiologic injury after reperfusion. an antioxidant combination was found to dramatically reduce cell death after reperfusion (74). it was noted that hypothermia induced by ice-water immersion could lower cerebral oxygen consumption in dogs. For example. a class of molecules that inhibit key components of the apoptotic pathway. these are not mutually exclusive categories. and apoptosis. Biochemistry A variety of biochemical changes provoked by IR are modified by hypothermia. Compromise of the BBB might provoke further injury by permitting blood-borne toxins to reach brain tissues (86). may also play an important separate or adjunct role to hypothermia in treating cardiac arrest in the future. Although these agents alone have not been shown in whole animal models to improve survival or other outcome measures after CA.77). it is possible that in the future they will play a supporting role to the induction of hypothermia. Given the importance of temperature in a wide range of physiologic processes. microsphere measurements in a dog model of CA demonstrated that hypothermia to 28oC led to better blood-flow characteristics during CPR (83). the groupings are somewhat arbitrary for the sake of discussion. which may in turn activate apoptotic machinery. Given the multitude of possible target effects.Chapter 15 / Therapeutic Hypothermia 259 mize IR injury and improve both survival and function (72. brain edema was also found to be reduced by hypothermia in a rat model of CA (82. hypothermia has been shown to lessen damage to the blood–brain barrier (BBB) caused by IR (82. Gross Physiology As early as 1954.84). hypothermia to 32oC reduced nitric oxide (NO) production as measured . MECHANISMS OF HYPOTHERMIC PROTECTION The mechanisms by which hypothermia may protect against ischemic injury are varied and incompletely understood. These agents are a subject of intense study (79. most of the data pertaining to mechanism of injury comes from studies of these tissues in stroke or MI models. Caspase inhibitors. hypothermia may represent “the ultimate neuroprotective cocktail” (25). it is reasonable to conclude that multiple mechanisms might be involved. future antioxidant therapies may specifically target injurious sources of oxidants although maintaining beneficial oxidant signaling (78).86).73). biochemistry. as well as injury and death (76. In a cardiomyocyte model of IR.25). Certainly. In a gerbil stroke model. Finally. Therefore. The specific targets and processes which hypothermia modulates can be crudely grouped into four categories: gross physiology. and have the potential to significantly attenuate IR injury. It is likely that oxidants play double-edged roles in both signaling and protective adaptation (75). Because brain and heart are generally understood to be the most sensitive organs to IR effects. and in a gerbil brain ischemia model (85). transcriptional/translational changes. by approx 7% per 1oC drop in temperature (81). redox changes in the cell may stimulate transcriptional/translational changes. animals subjected to mild hypothermia were found to have decreased arachidonic acid metabolism compared with normothermic controls (87).

c-jun.260 Cardiopulmonary Resuscitation in jugular blood (88). in theory cooling is not absolutely required to protect tissues during ischemia—as most experts believe it . Cellular Signaling Via Protein Changes Intracellular signaling can quickly and dramatically alter the array of gene transcription activity of a cell. as measured on autopsy in patients who died within days of resuscitation (106). Hypothermia may inhibit this process. is inhibited by hypothermia to 32oC in a rat brain IR model (111). c-fos. ATP depletion and free radical production might be universal mediators of IR damage. Fas ligand. glutamate release showed a direct correlation with brain temperatures from 31 to 39oC (97). The process of apoptosis is an active one.109. another crucial protein in the apoptotic machinery.105).103). a characteristic step in the apoptotic pathway. brain-derived neurotrophic factor. in heart. was increased in a rat model of CA when animals were cooled to 33oC (101). necessary to bind Fas ligand and initiate the apoptotic pathway. This cellular program can be activated as part of normal physiology such as during embryonic development. In a gerbil brain ischemia model. Fas receptor. An extracellular signaling molecule thought to protect against injury. a recent report showed that the apoptotic pathway enzyme caspase-3 was upregulated in brain tissue after resuscitation from CA.104. Other biochemical changes seem more likely to be directly linked to damage processes. such as the observation that hypothermia slows adenosine triphosphate (ATP) depletion during IR (89). A study of liver IR demonstrated a drop in c-jun terminal kinase activity at 25oC when compared to normothermic controls (100). Widespread evidence from animals also supports the notion that apoptosis is activated after reperfusion (48. In a CA mouse model. Free radical production also appears to be attenuated by hypothermic conditions in a rat cerebral ischemia model (90). and aspartic acid. or are chosen. both of which might be inhibited by lowered temperatures. and other tissues (91). brain. such as the neuron-excitatory amino acids glutamate. In fact. Proteolysis of the cytoskeletal protein fodrin. Although some suggestive data exists that the degree of apoptosis can be reduced by hypothermia. requiring protein synthesis and enzymatic activity. are reduced when neural tissues are cooled (92–94). glycine. The release of other mediators. which in turn can trigger a variety of injury processes. ischemic release of these neurotransmitters is quite sensitive to temperature (95. to die. To cite some human data as examples. A wide variety of evidence implicates the induction of apoptosis as a component of reperfusion injury (91.96). Whether these aforementioned alterations are simply markers of hypothermic effects or actually issues in reperfusion injury remains to be clearly established. or as an abnormal response in a wide variety of disease states (102. Apoptosis Programmed cell death is a complex yet ubiquitous process by which cells actively chose. and krox-24 (99). is elevated in blood after resuscitation from CA (107). Similarly. METHODS FOR SUSPENDED METABOLISM AND PROTECTION FROM ISCHEMIA WITH AND WITHOUT HYPOTHERMIA Although most methods for suspended animation use hypothermia. the topic certainly deserves more investigation in animal models.110). is upregulated in livers harvested from donors in CA (180). a group of signaling pathway genes known as the “immediate early genes” (98) were activated after resuscitation—specifically.

An interesting notion is that all these mechanisms are also potentially present in nonhibernators. although it is an important area of research. nonhibernating hearts develop elevated intracellular Ca. a highly purified plasma fraction from hibernating woodchucks has been reported along with an _1-glycoprotein-like 88kDa “hibernation-related protein” that may contain the triggering activity (116). and spontaneous Ca waves that have been suggested to initiate VF.” the b-opioid receptor-binding molecules have been identified as central to this response (114). because during arousal from hibernation. is seems likely that the full genomic/transcription/ translation machinery is potentially available in humans to use such mechanisms for ischemia tolerance. These limited methods include use of circulating cooling blankets containing . hibernation is an interesting model for reperfusion injury. Possible mechanisms include a resetting of the hypothalamic temperature set point. Experience to date with this notion is quite limited. who report that the neurotensin analog NT69L stimulated prolonged mild hypothermia (<35oC for nearly 300 minutes) in rats without the use of active cooling. Although the hibernating pathways may not be active in nonhibernators. reduced contraction force. then it should be possible to simulate the metabolic consequences of hypothermia without necessarily decreasing the actual temperature. By contrast hibernating animals fail to show these alterations in Ca with low temperatures and may even improve contractility at low temperatures (117). Most experts believe that during ischemia protective adaptive responses include: reducing energy utilization by shutting down nonessential cellular activities. Similar metabolic changes are produced during hypothermia as well as during hibernation in many hibernating animal species. with the result that mild hypothermia was produced without the need for a cooling device. which was in turn associated with improved outcomes after 8 minutes of asphyxial CA (113). If true. METHODS OF HYPOTHERMIA INDUCTION Most clinical studies of hypothermia induction have employed external means of cooling. Efforts to isolate and purify the protective proteins responsible for this protection are ongoing. An interesting approach to this is offered by Katz et al. Mechanisms used by hibernators to handle Ca include reducing Ca entry into the cell with channel alterations. reducing permeability of membranes to ion flux (thus reducing ATP required to maintain ionic gradients). With low temperatures. because many hibernators are also hypoxia tolerant. Calcium (Ca) is a critical intracellular messenger that is tightly regulated in cells universally and dysregulation is described with ischemia and reperfusion. Other laboratories have investigated the possibility of triggering natural hibernation pathway using a “hibernation-induction trigger. Another approach is to consider the mechanisms of altered calcium homeostasis during ischemia and reperfusion although noting that hibernating mammals have an enhanced capacity to maintain intracellular calcium homeostasis over nonhibernating mammals (such as humans). Reduction of infarct size from 65 to 27% and reduction in arrhythmias have been observed using b-opioid-receptor agonists administration (115). and synthesis of ATP via glycolytic pathways during low oxygen states (112). Additionally. enhancing Ca sequestration in the sarcoplasmic reticulum and increased removal (117). Natural hibernation has been suggested as an excellent model to study mechanisms of tissue protection during ischemia. full reperfusion occurs but with no detectable injury even after prolonged periods of ischemia (2).Chapter 15 / Therapeutic Hypothermia 261 is the metabolic consequences of hypothermia (not temperature itself) that causes protection.

Several companies have developed cooling catheter systems. Using aortic flush. The catheters that will prove more effective for localized cooling and for rapid induction of core hypothermia remains to be established. but to induce moderate hypothermia often takes at least several hours. Bernard has reported on a simple internal cooling technique. and will likely be a focus of intensive research over the next few years. Our laboratory has investigated the use of ice-water slurries to cool swine via the pulmonary route. was used to successfully cool rabbits from 39 to 35oC under normal physiologic conditions (125). preventing heat exchange.. low surface area) nature of the human trunk. showed that 20 kg dogs could be cooled to target temperatures of 34oC within 10 to 15 minutes (56). This method involves the administration of cold saline via an aortic balloon catheter. Although the method provides robust cooling. including cold air and cold liquids. One such PFC. access to the peritoneal space would be more readily achievable than aortic cannulation. One such commercially developed catheter has been used in swine and was able to cool 50 kg swine to a target temperature of 32oC within 60 minutes (121).118). Sterz. perfluorodecalin. or both (4). Another PFC. perflubron.17. some form of direct contact with cold water or ice (3. with cold saline infusion into the peritoneum in conjunction with external ice cooling.e. Safar and colleagues have pioneered rapid blood cooling in dogs via an “aortic flush” technique (5. which was able to cool dogs in VF to 34oC without significant adverse effects (120). administration of ice-cold saline (30 mL/kg) via a peripheral intravenous line. Radiant (SetPoint). such as MI and stroke (122. This technique grew out of experiments in the 1940s by Negovsky et al. including (a) the formidable ability of the human body to redirect blood flow away from cooled extremities or skin. in which retrograde arterial flush was used to treat soldiers suffering from exsanguination CA. External cooling of humans is difficult because of several reasons. such as an external cooling helmet which was able to cool core temperatures two to three degrees over 3 hours (54). Other groups have pursued a pulmonary cooling strategy. which resulted in 1. Behringer et al. We have demonstrated core brain-cooling rates of up to .7oC decrease in core temperature (119).119). thus cooling the brain and heart via retrograde flow. has been used in a liquid ventilation protocol to cool dogs during CA (124). (b) the relatively compact (i. a number of laboratories have begun to develop novel cooling methods. Another blood cooling method under development for resuscitation involves catheters with closed cooling systems. Innercool (Celsius Control). exploiting the enormous surface area at the alveolar–pulmonary capillary interface. Clinical experiments with a similar cooling catheter are underway in Europe (F. Perfluorocarbon (PFC) liquids have been under investigation for decades as possible blood substitutes and liquid ventilation media. More experimental methods have also been attempted. which occludes the descending aorta. carefully engineered microparticulate ice-water slurries with high flowability are instilled into the lungs of swine. including Alsius (Icy catheter). it requires rapid aortic access. These methods are reasonably successful at inducing mild hypothermia. among others. It should also be noted that catheter-based cooling is being tested widely in the clinical treatment of focal ischemic processes. and (c) the ability to generate thermal energy to defend against cooling. given their ability to act as oxygen and carbon dioxide carriers. Another invasive technique for cooling was attempted exploiting the peritoneal space.262 Cardiopulmonary Resuscitation either cold air or water (7. which may limit its development clinically. personal communication). In our experiments.123). Cooling via the pulmonary route can involve a variety of media.16. Given the limitations of external cooling described above.56). Certainly.

must become available to emergency medical service or even lay rescuers. If true. N Engl J Med 2002. 2. 4. another advantage of hypothermia induced during arrest (intra-arrest cooling) would be that it could allow for transport and placement of the patient on CPB support. 103:1182–1184. Bernard SA. overstimulation of the immune system. O’Shaughnessy M. First a method for rapid cooling very early. FUTURE OF HYPOTHERMIA AND SUSPENDED ANIMATION Several important enhancements are likely required before widespread hypothermia and suspended animation techniques can become a mainstream therapy. patients could be rapidly cooled to protect organs from ongoing ischemia and to buy time for additional therapies like establishment of CPB with controlled reperfusion. with improved artificial circulation. However. O’Sullivan ST. the greater is its benefit.8oC within 30 minutes during CPR (126). 34:446–449. 346:557–563. REFERENCES 1. Thus. HACA. in the metabolic phase of CA (128). loss of calcium homeostasis. Ann Plast Surg 1995. Suspended animation thus fits in nicely as a metabolic phase therapy with the notion of the three-phase time-sensitive model of CPR (128). Everything we know thus far about resuscitation would suggest that when earlier and faster hypothermia is accomplished. Workshop executive summary report: post-resuscitative and initial utility in life saving efforts (PULSE). leaky membrane integrity. Becker LB.Chapter 15 / Therapeutic Hypothermia 263 4. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. The current limitation to more widespread use of CPB is that it is currently difficult to initiate rapidly on patients (requiring often 45 minutes for establishment). Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. et al. et al. Although these may be sufficient to restore circulation with defibrillation in the circulatory phase (approximately during arrest intervals of less than 10 minutes). mediators of apoptosis. With the heart stopped and with full circulation provided by CPB. chest compression alone fails to restore most victims of CA beyond this time. . we know that relatively low cardiac outputs are produced in most cases. Other adjunctive techniques include retrograde blood flow as in arterial perfusion of the superior vena cava during aortic arch surgery (127). An additional requirement for suspended animation is a practical method to produce improved artificial circulation although the heart is stopped. Gray TW. 3. N Engl J Med 2002. as occurs with CPB. Circulation 2001. caspase activation and other biochemical pathways that lead to death if uncorrected. 346:549–556. O’Connor TP. survival appears promising (129). Budinger T. Although this is the purpose of classical chest compression CPR. The limits for reversal of acute death (and how long a person can survive CA) when treated under such a suspended animation paradigm remain to be discovered. This highlights the importance of bioengineering partnerships to advance new devices to overcome this thermodynamic challenge. Baron Larrey and cold injury during the campaigns of Napoleon. Buist MD. circulating cytokines. an effective method started by a lay-person on a victim of CA may result in far better outcomes than we currently see when cooling is performed slowly and relatively delayed following CA. full attention could go to reversal of metabolic injury caused by free radical generation. With the failure of defibrillation and circulation to restore a stable hemodynamic state. Weil MH. preferably in the field.

Connor EL. Balaji S. Ann Emerg Med 1993. Postischemic hypothermia. 14. 28:N214–N218. Orlowski JP. Curr Opin Crit Care 2001. Resuscitation 1998. Radovsky A. 51:350–355. 7. Cerebral resuscitation after cardiac arrest: research initiatives and future directions. Arch Surg 1964. 6. 29. 7:45–50. 23:1454–1462. Hypothermia and barbiturate coma for refractory status epilepticus. Holzer M. et al. 89:619–629. Behringer W. The genuine works of Hippocrates. Choi SC. Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. et al. II-368. 15. Mild resusitative hypothermia to improve neurological outcome after cardiac arrest: a clinical feasibilty trial. Optimal myocardial preservation: cooling. Klain M.264 Cardiopulmonary Resuscitation 5. 20. Anesthesiology 2001. Lenhardt R. cardioplegia. Barboso G. Stezoski SW. Protection against hippocampal CA1 cell loss by post-ischemic hypothermia is dependent on delay of initiation and duration. Fay T. Becker LB. Metab Brain Dis 1992. 26. 7:184–188. 38:542–550. Safar P. Crit Care Med 1996. Lischer CE. discussion 551. N Engl J Med 2001. 14:171–201. . Clinical trial of induced hypothermia in comatose survivors of outof-hospital cardiac arrest. Resnick DK. Suspended animation for delayed resuscitation from prolonged cardiac arrest that is unresuscitable by standard cardiopulmonary-cerebral resuscitation. 24: S81–S89. 95:531–543. Hornick R. 18. The effect of hypothermia on the incidence of delayed traumatic intracerebral hemorrhage. Sessler DI. 27. et al. 66:221–224. Neurosurgery 1994. 21:1348–1358. 24. Ann Thorac Surg 1996. Miller ER. Tisherman SA. Mol Neurobiol 1997. Zhao D. Bernard S. Sterz F. 31. Jr. et al. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective. Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. 24:382–388. Tisherman S. Ann Emerg Med 1997. 19. Cox WMJ. Sterz F. et al. 24: 911–914. Safar P. Complications and treatment of mild hypothermia. Zeiner A. Stroke 1992. 61:760–768. 9. Clifton GL. and conditioning. 8. Safar P. Markarian GZ. Crit Care Med 1993. 10. Kuboyama K. Circulation 2002. 12:367–372. Vanden Hoek TL. Cruse RP. Alexander H. 32. Erenberg G. Tisherman SA. Past and present in myocardial protection. Bazzett HC. Ann Thorac Cardiovasc Surg 2000. Induced hypothermia in intensive care medicine. Abella BS. Norio H. et al. JAMA 1938. Banerjee A. 23. Carotid endarterectomy under hypothermic extracorporeal circulation: a method of brain protection for special patients. Deanfield J. Kurz A. Horne MK. Selective brain cooling after cardiac arrest. Darby JM. Tisherman SA. Mueller AJ. 31:86–94. Study of Wound Infection and Temperature Group. Radovsky A. Henning G. Corbett D. 334:1209–1215. Sutherland G. Elman R. Stein DJ. 106:II-367. Yanagawa Y. Marion DW. 344:556–563. 21. Mortality in severe experimental burns as affected by environmental temperature. Carroll M. 17. Fragnito C. Therapeutic hypothermia after cardiac arrest. Crit Care Med 2000. Br Heart J 1991. Ishihara S. 30. Crit Care Med 1984. randomized study. Mild hypothermia: therapeutic window after experimental cerebral ischemia. Cleveland JC. 33. 30:146–153. 1941:292–297. 34:252–5. Adams F. Takaba T. Jones BM. Sullivan I. J Perianesth Nurs 2000. 33:311–314. Safar P. 12. Harken AH. 16. Blair E. J Cardiovasc Surg (Torino) 1992. discussion 255–256. Eisenburger P. Colbourne F. Beek O. Intra-arrest hypothermia prior to resuscitation confers improved survival in a mouse model of cardiac arrest. James I. Fesani F. 22:324–49. Resuscitative hypothermia. Anaesth Intensive Care 1996. 13. Wren KR.. Hypothermia in bacterial shock. Crit Care Med 1996. New York: William Wood. Lack of effect of induction of hypothermia after acute brain injury. The effect of heat on blood volume and circulation. Beghi C. 1886. Proc Soc Exper Biol Med 1942. Rowland RT. Bernard SA. Inoue K. Neurosurgery 1996. Stroke 2000. Ginsberg M. Moderate hypothermia in the management of resistant automatic tachycardias in children. Leonov Y. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Kuboyama K. 39:61–66. 22. Saccani S. N Engl J Med 1996. A critical appraisal with implications for clinical treatment. 111:1841–1845. Lueders H. 34. Holzer M. 15:151–155. 25. Lee JH. Weinrauch V. Detrimental effects of hypothermia: a systems analysis. Clinical report and evaluation of low temperature in treatment of cancer. Safar P. Marion DW. 11. Meldrum DR. Sessler DI. 6:3–8. Proc Inter St Post-grad Med Ass N Amer 1941. Hong SC. 28.

Reduction of reperfusion injury with mannitol cardioplegia. Vanden Hoek TL. Xiao F. et al Suspended animation for delayed resuscitation. N Engl J Med 1941. 224:281–288. Tisherman SA. Am J Emerg Med 1998. Maulik N. The use of hypothermia after cardiac arrest. Low PA. Terasaki H. Shao Z. Yee H. Uihlein A. Radovsky A. Marcus SG. Physiologic mechanisms of postischemic tissue injury. Sterz F. Safer P. 52:224–30. Riccio M. et al. 42. Greenwood WF. 45. Resuscitation 2001. 270:H1334–H1341. 43. Tanimoto H. Milde JH. 49. Anesthesiology 1980. Br J Plast Surg 1997. Lepore DA. 36. 122(Pt 1):161–169. Tollefsbol G. Yoshida T. Daw EF. Jr. Corbett RJ. Wilson YT. 38:423–428. 817:241–245. Ann Surg 1958. 52. Bellamy RF. Li C. 93:1491–1499. Pachter HL. Terry HR. J Trauma 1990. Granger DN. 1950. Mitsui Y. 42:17–23. 60. Prueckner S. Hypothermic aortic arch flush for preservation during exsanguination cardiac arrest of 15 minutes in dogs. Mild hypothermia protects against postischemic hepatic endothelial injury and decreases the formation of reactive oxygen species. 41. Sterz F. 191:650–656. Effect of cerebral and cardiac outcome. Canevari L. 48:77-83. Schmelzer JD. 54. The causes of death in conventional land warfare: implications for combat casualty care research. Talbott JH. indications and techniques. Radovsky A. Brain 1999. Spencer FC. Patel S. Induced hypothermia: Physiological effects. et al. Becker LB. 50. 39. A preliminary study. Laptook AR. 16:17–25. Mild hypothermia protects against ischaemia-reperfusion injury in rabbit skeletal muscle. Safar P. Moderate hypothermia after cardiac arrest of 17 min in dogs. Huyghens L. Lindsay WK. Mol Cell Biochem 1999. 48:163–174. Therapeutic deep hypothermic circulatory arrest in dogs: a resuscitation modality for hemorrhagic shock with ‘irreparable’ injury. Pediatr Res 1997. The physiologic and therapeutic effects of hypothermia. Topical hepatic hypothermia attenuates pulmonary injury after hepatic ischemia and reperfusion. J Trauma 1999. Schumacker PT. Safer P. Rapid hypothermic aortic flush can achieve survival without brain damage after 30 minutes cardiac arrest in dogs. Safar P. Burns DK. Ann Surg. Redox Rep 2000. Llesuy S. 5:303–310. Schwartz JD. Lancaster JR. Hachimi-Idrissi S. 31:1051–1061. 196:13–21. Zak R. Woods R. Das DK. 21:1600–1606. Michenfelder JD. The detrimental effects of prolonged hypothermia and rewarming in the dog. Crit Care Med 1996. Safer P. 44. Spencer FC. 47. 30:836–847. Leonov Y. Sterett R. Journal of Cerebral Blood Flow and Metabolism 1990. Kuboyama K. Williams GR. et al. . J Am Coll Surg 2000. et al. Kihara M. Yoshitake A. The clinical use of hypothermia following cardiac arrest. Mild protective and resuscitative hypothermia for asphyxial cardiac arrest in rats. Radovsky A. Radovsky A. 45:889–898. 61. Burgos M. Am J Phys 1996. et al. Safar P. Tisherman SA. Steen PA. Anesthesiology 2000. Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase. The effect of mild hypothermia and induced hypertension on long term survival rate and neurological outcome after asphyxial cardiac arrest in rats. 50:343–348. Kentner R. 40. 48. Benson DW. Bigelow WG. Safar P. 55. Ao H. et al. Bates TE. Brain Res 1999. 10:57–70. Peitzman A. Hypothermia: its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperature. et al. 132:849–866. 53. Garcia D. Moon JK. Modest hypothermia provides partial neuroprotection when used for immediate resuscitation after brain ischemia. Corne L. J Trauma 1991. Mil Med 1984. discussion 83–84. Tendi EA. 51. Hypothermic neuroprotection of peripheral nerve of rats from ischaemia-reperfusion injury. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs.Chapter 15 / Therapeutic Hypothermia 265 35. Reperfusion injury in cardiac myocytes after simulated ischemia. 46. Zollman PJ. Tisherman SA. Michenfelder JD. Annu Rev Physiol 1995. Bellamy R. Williams GR. 59. Effect of postischaemic hypothermia on the mitochondrial damage induced by ischaemia and reperfusion in the gerbil. Anesth Analg 1959. 58. Sterz F. Korthuis RJ. Leonov Y. Shamamian P. 148:462–468. Prueckner S. 57. Zar HA. Surg Clin North Am 1965. Long-term mild hypothermia with extracorporeal lung and heart assist improves survival from prolonged cardiac arrest in dogs. Clark JB. Profound hypothermia (less than 10°C) compared with deep hypothermia (15°C) improves neurologic outcome in dogs after two hours’ circulatory arrest induced to enable resuscitative surgery. Resuscitation 2001. 47:1028–1036. 49:73–82. Ferreira R. 38. Ann Thorac Surg 1989. Console A. 24:S24–S47. Stroke 1990. Behringer W. 57:311–332. 37. 149:55–62. 56.

Ishikawa T. 25:522–523. J Cereb Blood Flow Metab 1996. Transpl Int 2000 . Vanden Hoek TL. Ricci JE. Mild hypothermia induced before cardiac arrest reduces brain edema formation in rats. Xiao F. Nakakimura K. J Neuropathol Exp Neurol 1990. Halley M. 233:601–610. Nurse S. delayed postischemic hypoperfusion. Summary of the Fifth Annual Decade of the Brain Symposium. 83. Perng WC. Corbett D. 779:297–300. Rezaiefar P. Am J Physiol 1954. Schumacker PT. 284:H141–H150. Schumacker PT. Vanden Hoek TL. Li C. 14:620–627. In vivo myocardial infarct size reduction by a caspase inhibitor administered after the onset of ischemia. 71. 68:2089–2092. Matsumoto M. Mild intraischemic hypothermia reduces postischemic hyperperfusion. 86.092–18. Gallagher MA. Shao Z. Brain Res 1998. 27:105–113. Mild and moderate hypothermia provide better protection than a burst-suppression dose of thiopental against ischemic spinal cord injury in rabbits. 68. Combs DJ. 85. 16:474–480. initiates intrinsic apoptosis injury in chick cardiomyocytes. Trends Pharmacol Sci 1996. Anesthesiology 1981. 74. 82. Yan HC. Neuroprotection after several days of mild. 77. 64. Stroke 1994. 79. Adv Exp Med Biol 1994. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Huang JQ. Shao Z. 17:227–233. Wojcik K. Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted? Cerebrovasc Brain Metab Rev 1990. Effect of the no-flow interval and hypothermia on cerebral blood flow and metabolism during cardiopulmonary resuscitation in dogs. 76. 2:1–26. Narita K.098. Pharmacologically induced hypothermia for cerebral protection in humans. 273:18. Xiao F. Ferrari R. Delta opioid receptors and low temperature myocardial protection. Stroke 1996. et al. Roy MW. 70. Kubota M. Karibe H. Journal of Biological Chemistry 1998. 179:85–88. Mild hypothermia reduces the rate of metabolism of arachidonic acid following postischemic reperfusion. 86:534–540. and lidocaine. Koroshetz WJ. Arnold TC. Heros RC. Becker LB. Koehler RC. Donaldson DL. Caspase inhibition protects from liver injury following ischemia and reperfusion in rats. Stroke: early pathophysiology and treatment. blood-brain barrier disruption. Becker LB. 72. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. Reperfusion. 84. Sakabe T. Dietrich WD. Am J Physiol Heart Circ Physiol 2002. Preconditioning and postresuscitation injury. Radovsky A. and neuronal damage volume after temporary focal cerebral ischemia in rats. pentobarbital. Bolling SF. Cursio R. Li C. 80. Acad Emerg Med 2002. Ann Thorac Surg 1999. Li C. Qin Y. 87. Wu CP. Vanden Hoek TL. Maulik N. 160: 1319–1323. Vanden Hoek TL. 29:2571–2583. Young Y. Zarow GJ. 402:139–142. Shaffner DH. Kilgore KS. Zhang S. Traystman RJ. 69. Crit Care Med 2002. Chiang CH. Radinovic S. Stroke 1998. 55:263–268. Yu L. 49:486–497. Rosomoff HL. Moderate hypothermia reduces postischemic edema development and leukotriene production. Stroke 1994. 67. et al. et al. Am J Respir Crit Care Med 1999. 81. 25:1877–1881. 65. Das DK. 73. Buchan AM. brain edema. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Schumacker PT. Nakane M. Yu CP. Emerging treatments for stroke in humans. Weinstein PR. Busto R. Graham SH. Wu K. Antioxidant effectiveness in ischemia-reperfusion tissue injury. Becker LB. J Cereb Blood Flow Metab 1994. 86:1120–1127. 21:177–181. Shao Z. Holaday DA. Black SC. Circ Res 2000. Schwartz CF. Anesthesiology 1997. not simulated ischemia. Gugenheim J. . Astrup J. Oxygen-free radicals at myocardial level: effects of ischaemia and reperfusion. Georges AJ. Valdes I. Neurosurgery 1987. Significant levels of oxidants are generated by isolated cardiomyocytes during ischemia prior to reperfusion. Methods in Enzymology 1994. Dempsey RJ. Eur J Pharmacol 2000. et al. J Mol Cell Cardiol 1997. Safar P. Iida Y. Menon DK. Hypothermia and prostaglandin E(1) produce synergistic attenuation of ischemia-reperfusion lung injury. Maley ME. Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. 29: 2607–2615. 9:105–114. 75. Moskowitz MA. Sano T. 78. drug-induced hypothermia. The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. Sorensen PM. Sorensen HR. Vanden Hoek TL. 30:S172–S175. Cowen DE. 66. 63. et al.13 (Suppl 1):S568–S572. 366:99–111. Eleff SM.266 Cardiopulmonary Resuscitation 62. Inhibition of cerebral oxygen and glucose consumption in the dog by hypothermia.

Nakashima K. 97. Stroke 1989. Filiano AJ. 104. Nakamura N. Neurosurgery 1996. Globus MY. Rothwell NJ. Krumnikl J. 111. Neuroscience 1991. Jr. Todd MM. Global cerebral ischemia due to cardiocirculatory arrest in mice causes neuronal degeneration and early induction of transcription factor genes in the hippocampus. 78:1389–1399. Opiate drugs and delta-receptor-mediated myocardial protection. Lentsch AB. Stroke 1996. Tsuruta R. 100:II357–II360. Edwards MJ. Kumura E. Hicks SD. Hengartner MO. Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation. Richelson E. beta. MacKenzie A. Programmed cell death in animal development. Fertig KC. J Neurochem 2001. 7:1465–1468. Berlin: Springer. Nature 2000. Piantadosi CA. Grafe MR. Collard CD. 114. 92. In: Yearbook of Intensive Care and Emergency Medicine. The biochemistry of apoptosis. 11:2495–2499. Flentjar NJ. High serum soluble Fas-ligand in cardiopulmonary arrest patients. Winfree CJ. Minor T. Papadopoulos MC. 14:305–312. Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Abella BS. Vincent JL. Baker CJ. gamma isoforms and fodrin proteolysis in rat brain synaptosome during ischemiareperfusion. 88:347–354. Dietrich WD. Hirner A. Mol Brain Res 1999. Katz LM. 112. Benedict MB. Acad Emerg Med 2001. 1:233–240. Defense strategies against hypoxia and hypothermia. Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits. Zornow MH. Circulation 1999. Kato A. Solomon RA. Mild hypothermia reduces penumbral glutamate levels in the rat permanent focal cerebral ischemia model. Kosaka H. Science 1986. Glatzel U. 18:348. 65:135–142. An introduction to the changes in gene expression that occur after cerebral ischaemia. ed. Mitani A. Lundberg J. Böttiger B. S. 98. Giffard RG. An ICE inhibitor. Critical levels of extracellular glutamate mediating gerbil hippocampal delayed neuronal death during hypothermia: brain microdialysis study. Shiga T. Kil HY. 103. J Cereb Blood Flow Metab 2002. 108. Bolli R. 20:904–910. 106. 16:100–106. Zhang J. 100. 93.Chapter 15 / Therapeutic Hypothermia 267 88. Hearse DJ. D’Cruz BJ. 231:234–241. 107. Baker AJ. Kataoka K. Callaway CW. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Pathophysiology. Srinivasan A. 89. clinical manifestations. . 110. Cell 1997. Singh S. Tohma J. Weil M. 95. Anesthesiology 2001. Hypothermia inhibits translocation of CaM kinase II and PKCalpha. Harada K. Fas receptor is upregulated in livers from non-heartbeating donors. G. 21: 366–373. Stroke 1991. Am J Emerg Med 2000. Activation of caspase-3 in permanent and transient brain ischaemia in man. et al. Yoshimine T. Effect of hypothermia on the ischemic and reperfused rat skeletal muscle. Busto R. 2002. pp. 113. Benedict PE. Fiore AJ. Neuroreport 2000. 94. Ishikawa T. monitored by in vivo (31)P-magnetic resonance spectroscopy. 42:661–670. 90. 94:1133–1138. 109. 22:666–673. 220:45–48. Bolling SF. Neurotensin analog NT69L induces rapid and prolonged hypothermia after hypoxic ischemia. et al. Hayakawa T. 38: 1216–1222. 96. Elander A. J Cereb Blood Flow Metab 1996. Love S. Marsala M. Br J Neurosurg 2000. Ischemia-Reperfusion and Acute Apoptotic Cell Death. Tolba R. 105. 3–11. Connolly ES. Soussi B. McMahon B. Trends in Cardiovascular Medicine 1991. Loddick SA. Taylor JM. Cell Mol Neurobiol 1999. Raff MC. 33:327–33. et al. Hypothermia prevents biphasic glutamate release and corresponding neuronal degeneration after transient spinal cord ischemia in the rat. 282:G608–G616. Am J Physiol Gastrointest Liver Physiol 2002. Jacobson MD. Takaoka M. Microsurgery 2001.. Maekawa T. Barber R. 407:770–776. Teschendorf P. et al. McLeish KR. z-VAD-DCB attenuates ischaemic brain damage in the rat. 8:1115–1121. 22:843–851. Hochachka PW. Crack PJ. Bell BA. DeFranco DB. Becker LB. Su TP. Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. Neurosci Lett 1996. Wang Y. Eur Surg Res 2001. Reperfusion induced injury: manifestations. 27:913–918. 67:664–669. Neuroreport 1996. J Neurosci Res 2002. Schnurr C. Wilcock GK. mechanisms. and prevention of ischemia-reperfusion injury. 102. 19:199–208. et al. Hypothermia suppresses nitric oxide elevation during reperfusion after focal cerebral ischemia in rats. 99. Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury. Mechanisms of hypothermic protection against ischemic liver injury in mice. 91. 101. Iwama H. and clinical relevance.

120. Sessler DI. et al. infarct size. 282:H1584–H1591. Resuscitation after cardiac arrest: a 3-phase time-sensitive model. 104:1141–1147. Kirsch M. Stillson CA. Bernard S. Xiao F. De Georgia MA.5C/min) minimally invasive induction of hypothermia using cold perfluorochemical lung lavage in dogs. Peritoneal cooling for mild cerebral hypothermia after cardiac arrest in dogs. 104:1799–1804. Adaptive mechanisms of intracellular calcium homeostasis in mammalian hibernators. 118. Isolation and partial characterization of an opioid-like 88 kDa hibernation-related protein. Anesth Analg 2002. Russell S. Felberg RA. Cheng H. 50:364–370. Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. 128. et al. 282:H1953–H1960. 123. Gao DW. Dobak J. Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol. Yon S. Safety and performance of a novel intravascular catheter for induction and reversal of hypothermia in a porcine model. J Thorac Cardiovasc Surg 1992. Chair K. Krieger DW. Rapid (0. Chuang R. Alexander H. et al. Comp Biochem Physiol B Biochem Mol Biol 1998. 125. Resuscitation 2001. Oeltgen PR. Circulation 2001. 126. Smith K. Iaizzo PA. Hong SB. 122. 116. Shim TS. 129. 119. Krieger DW. Kasza K. Dae MW. Wowk B. Buckberg GG. J Exp Biol 2002. Becker LB. 16:246–251. Allen BS. 119:787–805. and cardiac output in human-sized pigs. Monteiro O. Sigg DC. Logan DL. 30:51–59. Weisfeldt ML. 56:9–13. Kaftani DJ. Beyersdorf F. ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. et al. 32:1847–1854. Role of delta-opioid receptor agonists on infarct size reduction in swine. 117.. Physiologic characteristics of cold perfluorocarbon-induced hypothermia during partial liquid ventilation in normal rabbits. et al. table of contents. Rapid induction of hypothermia using phase-change ice slurry: targeted cooling of the heart and brain during cardiac arrest. Inderbitzen B. Darwin M. Neurosurgery 2002. Horton ND. Abou-Chebl A. Circulation 2000:A2769. 288:3035–3038. 205:2957–2962. 94:157–162. Coles JA. 121.268 Cardiopulmonary Resuscitation 115. Resuscitation 2003. Jr. Stroke 2001. O’Farrell J. . Koh Y. 50: 189–204. JAMA 2002. Safar P. Jayakar D. Fletcher M. Am J Physiol Heart Circ Physiol 2002. Wang SQ. 124. Bruce DS. Effect of endovascular cooling on myocardial temperature. Steinberg GK. 127. Am J Physiol Heart Circ Physiol 2002. Hilgenberg AD. Perl J. Buist M. Resuscitation 1995. Warm glutamate/aspartate-enriched blood cardioplegic solution for perioperative sudden death. Zhou ZQ. Harris S. Results of aortic arch repair with hypothermic circulatory arrest and retrograde cerebral perfusion. Lakatta EG. Becker L. J Card Surg 2001. Induced hypothermia using large volume. Lasheras J.