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This chapter will describe the background of therapeutic hypothermia with regard to animal models with cardiac arrest or vessel occlusion that led to the recent trials of therapeutic hypothermia after cardiac arrest in humans (–). In addition, future potentials of intra-ischemic hypothermia (suspended animation) are discussed.

The single most important clinically relevant cause of global cerebral ischemia is cardiac arrest. Other causes like hanging will not be covered in this chapter. The estimated rate of sudden cardiac arrest lies between 40 to 130 cases per 100,000 people per year in industrialized countries (,). Unfortunately full cerebral recovery is still a rare event. Almost 80% of patients who initially are resuscitated fiom cardiac arrest remain comatose for more than one hour. One year after cardiac arrest only 10–30% of these patients survive with good neurological outcome (). Current therapy after cardiac arrest has concentrated on resuscitation efforts () but until recently no specific therapy for brain resuscitation was available.

Hypothermia can be neuroprotective when applied during or after focal cerebral ischemia. Its neuroprotective effect is especially robust in the laboratory where it has been shown to ameliorate many of the damaging effects of cerebral ischemia. Most laboratory research on therapeutic cooling in stroke models has been conducted in rodent models of temporary and permanent middle cerebral artery occlusion. Intra-ischemic cooling vastly reduces infarct size in most occlusion models. Although hypothermia has effects on excitotoxicity, apoptosis, inflammation, and the breakdown of the blood-brain barrier, any of which may lead to protection, the exact pathophysiologic mechanisms of protection by hypothermia during and after ischemia remain a matter of debate. This chapter will summarize potential mechanisms underlying the protective effect of hypothermia in focal cerebral ischemia.

Acute ischemic stroke is a major leading cause of death and disability throughout the developed world. Although early vascular reperfusion improves the clinical outcome, fewer than 5% of patients with acute ischemic stroke actually receive thrombolytic therapy. The challenge of thrombolytic therapy is that, with time, the ability to recover brain tissue decreases rapidly while vulnerability to reperfusion injury increases. The result of this quandary, a narrow time-window, proved to be the stumbling block in wider dissemination of this treatment. Conceivably, co-administration of a “tissue protectant” could enhance the effectiveness of thrombolysis while expanding the time window and reducing the risks of reperfusion. A promising candidate to serve this purpose is hypothermia. A wealth of animal experiments have demonstrated that hypothermia or simply fever prevention diminishes ischemic damage with transient occlusion followed by reperfusion. In models of permanent occlusion, reduction of infarct size was less impressive (, ). In transient ischemia models, hypothermia was most effective when administered during the period of vascular occlusion (intra-ischemic) or immediately after vascular reperfusion (post-ischemic) (–). According to these models, hypothermia is efficacious in concert with reperfusion in only a narrow time window. Some investigations suggest that more prolonged periods of hypothermia enhance the benefit of early post-ischemic induction and even may have benefit after permanent occlusion. Consequently, in patients with acute stroke, therapeutic hypothermia will more likely confer benefit in conjunction with early vascular reperfusion and when applied over prolonged periods of time. The use of antipyretic agents has not been shown to effectively reduce core temperature after stroke, although, post-stroke fever can be inhibited. Therapeutic mild (33–36°C) to moderate (28–32°C) hypothermia can be achieved by surface cooling (external cooling) or by using intravenous counter-current heat exchange (endovascular cooling). External cooling is almost invariably associated with imprecise timing and continuation of the hypothermic effect. With endovascular cooling heat is directly removed from, or added to, the thermal core, thus bypassing the heat sink and insulating effects of peripheral tissues. Several early open and controlled studies have shown that endovascular cooling is safe and can effectively manage core temperatures in the mild to moderate hypothermic range. This review of clinical studies will address the advances in the understanding of mechanisms by which hypothermia enhances stroke outcomes and how these insights may help to translate benefits of hypothermia from bench to bedside.

This chapter will address the use of therapeutic hypothermia in traumatic brain injury (TBI). Hypothermia has a long-standing history of clinical use in the management of patients with severe TBI, specifically as a second tier therapy in the treatment of refractory intracranial hypertension. The resurgence in the interest in the use of mild and moderate hypothermia in experimental cerebral ischemia and cardiac arrest in the late 1980s and early 1990s (culminating in its recent successful translation to clinical use for cardiac arrest) prompted parallel investigation in TBI beginning in 1991. This chapter will focus on that work—specifically, both laboratory and clinical investigation in the use of therapeutic hypothermia in TBI since 1991.

The treatment of traumatic brain injury (TBI) using hypothermia was first described by Temple Fay in 1943 (). In the 1950s, Sedzimir noted “better than expected” outcomes in several patients with TBI after lowering their body temperatures to between 27° and 30°C for 1 to 5 days (). Reports of contemporaneous research suggest that this pioneering use of hypothermia was based on the premise that TBI causes a hypermetabolic state, and that an increase in cerebral blood flow in response to the increased metabolic demand is responsible for the brain swelling associated with TBI. In uninjured dogs, for example, Rosomoff found that both cerebral blood flow and the cerebral metabolic rate for oxygen fell 6.7% for every 1°C reduction in body temperature between 35° and 25°C (, ). Stone and co-workers reported that cooling to 30°C in a primate model produced a 50% reduction in the cerebral metabolic rate for oxygen and a significantly lower rate of adenosine triphosphate depletion (). According to Lundberg in 1959, hypothermia was as effective as osmotic diuretics for reducing elevated intracranial pressure (ICP) and had a more prolonged ICP-reducing effect than hyperventilation (). James and colleagues found that hypothermia lowered the ICP in 20 of 40 patients with severe TBI; the ICP reduction averaged 51% ().

Therapeutic hypothermia as a potential treatment for spinal cord injury (SCI) has a long history. In early studies by Albin and colleagues (–), selective spinal cord cooling to approximately 12°C resulted in marked neurological and functional recovery after SCI. In a study by Green and colleagues (), regional hypothermia (6–18°C) in cats initiated 1 hr post-injury decreased edema formation and hemorrhage. In studies by Wells and Hansebout (5), local cooling to 6°C was also reported to be effective in minimizing functional deficits in dogs, even when initiated 4 hr after spinal cord compression. Taken together, these early investigations support the use of profound hypothermia as a therapeutic strategy to protect the spinal cord after injury. Nevertheless, producing profound local hypothermia of the injured spinal cord presents various technical problems, and the alternative use of systemic hypothermia can lead to potentially serious complications. Because the beneficial effects of hypothermia have been somewhat inconsistent in laboratory experiments, and some clinical studies lacked adequate controls, it is currently difficult to determine the degree of benefit with hypothermic therapy after SCI.

The first resuscitation societies, founded in the mid-18th century, were organized networks of rescuers responding primarily to drowning victims. In the 19 century, the development of general anesthesia and its attendant airway mishaps generated additional enthusiasm for preventing, understanding, and treating asphyxia. Thus, asphyxia was the main focus of early resuscitation science. More recently however, sudden collapse, primarily as a result of cardiac arrhythmia, has become the focus of resuscitation research and interventions. Reasons for focusing on sudden arrhythmic death include: 1) arrhythmia is more common than asphyxia as a cause of death in adults, 2) when the collapse is sudden and witnessed there is a precise epidemiologic definition for start and duration of ischemia, and 3) defibrillators for treatment of ventricular fibrillation (VF) or ventricular tachycardia (VT) have been developed and deployed worldwide. In addition, prospective clinical trials are strengthened by the selection of relatively homogenous patient populations and the use of discrete, measurable outcomes (e.g. defibrillation). Accordingly, the recently performed clinical trials of induced hypothermia following cardiac arrest (discussed in Chapter 2) excluded asphyxial arrest and limited enrollment to a highly-selected population of patients resuscitated from VF/VT.

Moderate to severe hypoxic-ischemic encephalopathy continues to be an important cause of acute neurologic injury at birth, occurring in approximately 1 to 2 cases per 1000 term live births (). The possibility that hypothemia might be able to alleviate neonatal brain injury is a ‘dream revisited’. Early experimental studies, mainly in altricial species such as kittens, demonstrated that hypothermia greatly extended the ‘time to last gasp’ and improved outcomes (). These findings led to a series of small uncontrolled studies in the 1950s and 1960s where infants not breathing spontaneously at five minutes after birth were immersed in cold water until respiration resumed (–). Although outcomes were said to be better than for historical controls, this experimental approach was overtaken by two major developments: the introduction of active ventilation of infants exposed to asphyxia and the recognition that even mild hypothermia is associated with increased oxygen requirements and greater mortality in the premature newborn (). Thus resuscitation guidelines for the newborn exposed to asphyxia have, until very recently, simply emphasized prevention of hypothermia.

The first example of hypothermia being used for therapeutic use dates back to the Edwin Smith papyrus, which described the use of cold applications to wounds of the head. Hypocrites advocated packing patients in snow and ice to reduce hemorrhage (). Later, during the War of 1812, Napoleon’s Surgeon-General, Baron Larrey, noted that soldiers who were closest to the fire died more rapidly than those who remained more hypothermic (). The latter observations may have been related to beneficial physiologic effects of hypothermia or the detrimental effects of superficial warming leading to afterdrop. During the French-Indochina war in the 1950s, the French attempted to use hypothermia for their soldiers unable to tolerate anesthesia and surgery at normal body temperature ().