Mild hypothermia

Han HS, Karabiyikoglu M, Kelly S, Sobel RA, Yenari MA. Mild hypothermia inhibits nuclear factor-kappab translocation in experimental stroke. J Cereb Blood Flow Metab 2003 23 589-598. 

Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA. Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience 2002 114 1081-1090. 

Han HS, Qiao Y, Karabiyikoglu M, Giffard RG, Yenari MA. Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. J Neurosci 2002 22 3921-3928. 

Markarian GZ, Lee JH, Stein DJ, Hong SC. Mild hypothermia therapeutic window after experimental cerebral ischemia. Neurosurgery 1996 38 542-550 [discussion 551]. 

Els T, OehmE, Voigt S, Klisch J, Hetzel A, Kassubek J. Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis 2006 21(l-2) 79-85. 

In 1987, however, a study by Busto et al. (5) showed that small decreases in brain temperature (as little as 2-5°C below normal brain temperature) conferred a marked protective effect against experimental global cerebral ischemia. This finding, as well as subsequent animal studies that modeled neurodegenerative diseases and CNS injury, led to a resurgence of interest in mild hypothermia as a method of cerebral protection. 

The neuroprotective properties of mild hypothermia have been demonstrated in numerous experimental animal models. Research in this area has been conducted for many years, yet the mechanisms of cerebral protection by mild hypothermia remain unclear and continue to be the subject of intense investigation. The neuroprotective effects of mild hypothermia have been attributed to alterations in metabolic rate (24), neurotransmitter release (25-27), activity of protein kinases (28), resynthesis of cellular repair proteins (29), cerebral blood flow (30), preservation of the blood-brain barrier (BBB) (31), attenuation of inflammatory processes (32,33), and decreases in free radical production (34). Although these may all be components of a complex cascade leading to neurologic injury, it has become increasingly clear that the primary mechanism of action of hypothermia may be different at various temperatures as well as under different ischemic and traumatic conditions. 

Despite the variability in animal models, the ultimate goals of experimental studies on mild hypothermia are essentially the same ... 

Define the critical period during which mild hypothermia has to be instituted to achieve neuroprotection—the so-called therapeutic window. ... 

Characterize the various physiological changes resulting from mild hypothermia under each experimental ischemic condition including effects on metabolism, cerebral blood flow, and BBB alterations. 

Elucidate the cellular and molecular mechanisms of hypothermic neuroprotection to optimize the use of mild hypothermia as a neuro-protective strategy. 

The study of mild hypothermia in animal models requires an understanding not only of the clinical features that are to be replicated, but also of species-specific metabolic and behavioral patterns of the animals being used as well as proper endpoints. The successful transition from the laboratory to the clinical arena depends on a continuous exchange of information between clinical investigators and basic scientists. 

Discrepancies between results from the preliminary studies and the larger, multicenter trials remain to be elucidated. Significant intercenter variance in patient management (fluids, mean arterial blood pressure, ICP, and CPP) and treatment may have adversely affected the results of one of these trials (The National Acute Brain Injury Study Hypothermia) (61). Despite the overall negative findings, however, it is quite possible that certain subgroups of patients may benefit from treatment with mild hypothermia. 

Recently, two landmark prospective randomized controlled studies were published demonstrating the benefit of mild hypothermia in improving neurologic outcome in patients suffering cardiac arrest from ventricular fibrillation (73,74). 

Komatsu Y., Fujita K., and Iguchi M. (2000) Mild hypothermia as a protective therapy for severe subarachnoid hemorrhage. Surg. Cereb. Stroke 29,16-20. 

Nagao S., Me K., Kawai N., et al. (2000) Protective effect of mild hypothermia on symptomatic vasospasm a preliminary report. Acta Neurochir. Suppl. 76,547-550. 

OhtsukiN., KimuraS., Nezu A., and Aihara Y. (2000) [Effects of mild hypothermia and steroid pulse combination therapy on acute encephalopathy associated with influenza virus infection report of two cases]. No To Hattatsu 32, 318-322. 

Chopp M., Knight R., Tidwell C. D., Helpern J. A., Brown E., and Welch K. M. (1989) The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat comparison to normothermia and hyperthermia. J. Cereb. Blood Flow Metab. 9, 141-148. 

Busto R., Globus M. Y., Dietrich W. D., Martinez E., Valdes I., and Ginsberg M. D. (1989) Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20, 904-910. 

Lo E. H., Steinberg G. K., Panahian N., Maidment N. T., and Newcomb R. (1993) Profiles of extracellular amino acid changes in focal cerebral ischaemia effects of mild hypothermia. Neurol. Res. 15, 281-287. 

Yamashita K., Eguchi Y., Kajiwara K., and Ito H. (1991) Mild hypothermia ameliorates ubiquitin synthesis and prevents delayed neuronal death in the gerbil hippocampus. Stroke 22, 1574-1581. 

Maier C. M., Sun G. H., Cheng D., Yenari M. A., Chan P. H., and Steinberg G. K. (2002) Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. Neurobiol. Dis. 11, 28 -2. 

Shiozaki T., Sugimoto H., Taneda M., et al. (1993) Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. J. Neurosurg. 79, 363-368. 

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