**Therapeutic Hypothermia in Acute Stroke**

Edgar A. Samaniego

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51071

## **1. Introduction**

Stroke is the second most common cause of death and a major cause of serious long-term disability in adults in industrialized countries. Approximately 90% of strokes are ischemic and the rest are hemorrhagic.[1] Unfortunately, few effective treatments can be offered during the acute and subacute phases. Since the introduction of tissue plasminogen activator (tPA) in 1995, there are no other medical treatments for ischemic stroke besides the use of antiplatelets for primary and secondary prevention. Moreover, the clinical treatments for hemorrhagic stroke are also limited.

In ischemic stroke most of therapies aim to recanalize the vessel and restore flow through pharmacological or endovascular treatments. However, another approach to preserve brain tissue is through the interruption of catalytic pathways triggered by ischemia. Rapid restoration of oxygen and glucose by thrombolysis will always provide the most effective neuroprotection, but directly targeting the brain parenchyma to confer neuroprotection may be a viable alternative, particularly in conjunction with thrombolysis. Multiple pharmacological attempts have failed in finding an ideal neuroprotective agent. Over 1000 neuroprotective agents have been tested in basic stroke studies with many showing promise.[2] However, to date no neuroprotective agent has successfully transitioned from bench or animal studies into clinical use. Although cooling may be unable to salvage neural tissue that has irreversibly progressed to infarction, hypothermia minimizes the extent of secondary injury as an acute or subacute treatment strategy. Hypothermia is increasingly being used, especially since therapeutic mild hypothermia has demonstrated to positively influence neurological outcome in humans following acute brain injuries, namely, global ischemic brain injury due to cardiac arrest and hypoxic-ischemic encephalopathy in neonates.[3, 4]

Catalytic cascades are generated in the brain tissue surrounding a blood clot after intracerebral hemorrhage (ICH). Hypothermia may also be used as a neuroprotection

© 2013 Samaniego, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Samaniego, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

treatment in these circumstances. Hypothermia has the potential to minimize secondary injury resulting from insufficient cerebral perfusion pressure or mechanical compression from herniation by ICH. Hypothermia preserves autoregulation of the cerebral vasculature and reduces cytotoxic edema around the hemorrhagic clot.[5]

Therapeutic Hypothermia in Acute Stroke 53

slows the rates of metabolite consumption and lactic acid accumulation and reduces cerebral

Hypothermia not only protects the brain by reducing cerebral metabolism during conditions of reduced substrate and shift to anaerobic glycolysis. Hypothermia also suppresses the accumulation and release of glutamate.[18] ATP loss during ischemia leads to ions flowing down their concentration gradients, and eventual efflux of potassium and influx of sodium and calcium.[19] Calcium influxes lead to direct neurotoxicity as well as extracellular accumulation of glutamate, which are neurotoxic. Experimental studies have shown that mild to moderate hypothermia attenuates the initial and delayed rise of extracellular potassium and prevents intracellular calcium accumulation, thus leading to decreased

Numerous studies have shown that hypothermia reduces the generation of reactive oxygen species, decreases brain edema, and prevents blood-brain barrier breakdown.[18] One potential mechanism is that hypothermia inhibits matrix metalloproteinases and preserves basal lamina proteins after stroke.[20-22] Moreover, a clinical study of 10 patients with large strokes who underwent mild hypothermia demonstrated lower levels of matrix metalloproteinase than normothermic patients.[23] Serum metalloproteinases are a good

Hypothermia has been documented by numerous investigators to alter gene expression normally observed after brain ischemia. Whereas a majority of genes are downregulated by hypothermia, a number of genes are also upregulated. [24] Interestingly, many proinflammatory and proapoptotic genes tend to be downregulated.[25-27] Whereas those

Additionally, hypothermia has been shown to inhibit activation of the inflammatory transcription factor nuclear factor kappa B via temperature-dependent inhibition of its inhibitor protein's kinase. Other studies indicate that hypothermia has antiapoptotic effects such as reduction of cytochrome C release, and inhibition of caspases and proapoptotic

Therapeutic hypothermia is defined as an intentionally induced, controlled reduction of a patient's core temperature below 36**°**C. Further classification includes mild (34**°**C–35.9**°**C), moderate (32**°**C–33.9**°**C), moderate/deep (30**°**C–31.9**°**C), and deep (< 30**°**C) hypothermia. [38]

In general, hypothermia appears to be effective whether the brain is cooled to 33°C or 28°C, but temperatures on the lower end appeared to be most effective according to a recent metaanalysis of the experimental literature.[39] However, lower temperatures are associated with a higher incidence of complications, require more sedation and sometimes even induction of

metabolic oxygen consumption, while improving glucose utilization.[11]

glutamate efflux and finally neuroprotection.

marker of blood-brain barrier breakdown.[20]

genes.[33-37]

**4. Cooling temperatures** 

genes that contribute to cell survival seem to be upregulated. [28-32]

paralysis accompanied by intubation and ventilatory support.
