Stroke 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. 

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. 

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

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. 

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., Ahem K., Cheng M. L., Lee J. E., Yenari M. A., and Steinberg G. K. (1998) Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke 29, 2171-2180. 

Weinrauch V., Safar P., Tisherman S., Kuboyama K., and Radovsky A. (1992) Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. Stroke 23,1454-1462. 

Graf R., Matsumoto K., RisseF., RosnerG., andHeiss W. D. (1992) Effect of mild hypothermia on glutamate accumulation in cat focal ischemia. Stroke 23, 150. 

The main role of mild hypothermia against stroke may, perhaps, be to extend the therapeutic window of other treatment modalities. On the other hand, hypothermia is by far the most potent neuroprotectant available against experimental cerebral ischemia, and new technological advances are now facilitating its implementation in the clinical setting. Understanding the mechanisms by which mild hypothermia exerts its neuroprotective effects will allow us to optimize its use as a therapeutic strategy. 

A large effort examining the potential efficacy of mild hypothermia to protect neurons from ischemic injury has shown promise in experimental stroke models and is now being translated into clinical trials. To develop the use of mild hypothermia as an efficacious and safe... 

Yenari M. A., Iwayama S., Cheng D., et al. (2002) Mild hypothermia attenuates cytochrome c release but does not alter Bcl-2 expression or caspase activation after experimental stroke. J. Cereb. Blood Flow Metab. 22, 29-38. 

Safar P., Xiao F., Radovsky A., et al. (1996) Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 27, 105-113. 

Yanamoto H., NagataL, Niitsu Y., et al. (2001) Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia. Stroke 32, 232-239. 

The effect of hypothermia in combination with thrombolytics has also been evaluated in only a few experimental studies. Meden et al. (11) studied differences in thrombolytic effectiveness in a rat embolic stroke model. In this study, 2 h of intraischemic hypothermia was administered with or without thrombolytic therapy. Thrombolysis was initiated at 2 h after ischemia onset. The investigators found that both hypothermia and thrombolysis significantly reduced infarct volume, but they could not demonstrate any added benefit of thrombolysis over hypothermia alone. A recent study by Wang et al. (12) used a focal embolic brain ischemia model to study the effects of minocycline, an antiinflammatory agent, alone or in combination with mild hypothermia (34—35°C started 1 h after embolization, 2-h duration). The results showed that both minocycline and the hypothermia-minocycline combination reduced infarct volume significantly, but no additive effect was observed. 

Schmid-Elsaesser R., Hungerhuber E., Zausinger S., Baethmann A., and Reulen H. J. (1999) Combination drug therapy and mild hypothermia a promising treatment strategy for reversible, focal cerebral ischemia. Stroke 30, 1891-1899. 

Wang C. X., Yang T. and Shuaib A. (2003) Effects of minocycline alone and in combination with mild hypothermia in embolic stroke. Brain Res. 963, 327-329. 

Schwab et al. used mild hypothermia (33-34°C) in 20 patients with acute severe middle cerebral artery (MCA) infarction for 48-72 h and found mild hypothermia to be safe and feasible (38). Schwab subsequently reported a series of 25 patients with severe MCA infarction treated with the same protocol (39). Intracranial pressure (ICP) was monitored for 3-7 d, and was found to decrease with initiation of hypothermia. ICP increased during re warming in several patients, but not to the levels seen prior to induction of hypothermia. Pneumonia was seen in 40% of patients treated with hypothermia in this trial, which is within the expected range of occurrence in patients with prolonged ventilation (40). Shimizu et al. used mild hypothermia (33°C) in five patients with embolic infarctions involving the internal carotid artery and MCA territories. The hypothermia was maintained for 3-7 d (41). It was found to be safe, but the number of patients was too small to report any efficacy. Another acute stroke trial using convection air to induce mild hypothermia without anesthesia was found to be feasible (42). Temperatures in this trial were reduced only to 35.5°C, and shivering... 

Hypothermia in stroke and head-injured patients is started as soon as possible after injury, and continues for the duration selected by the investigator. Each patient undergoing treatment with mild hypothermia should be paralyzed and sedated to prevent discomfort and reduce shivering. Unfortunately, this can compromise accurate evaluation of the neurological status in patients with acute head injury or stroke. Therefore, continuous monitoring of ICP is important in these intensive care unit patients. Because these patients are paralyzed and sedated, continuous mechanical ventilation is also necessary. Neuromuscular blocking... 

Deliberate mild hypothermia has been shown to be an extremely effective means of neuroprotection during periods of ischemia in experimental models. Intraoperative mild hypothermia has become a standard of practice for many neurosurgeons performing complex intracranial procedures. Recent findings of neurologic benefit in prospective, randomized, controlled clinical studies of cardiac arrest patients are encouraging, but more research is required to confirm and extend these positive results to other patients with stroke and traumatic insults. Further investigation must be completed to establish the optimal time and duration when treatment should be instituted to offer the optimal protection for patients with acute ischemic and traumatic injuries. 

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