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Introduction

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A 46-year-old woman was brought back to the neurologic intensive care unit after undergoing coiling of a right middle cerebral artery aneurysm that had ruptured the previous day. On examination, she required mild sternal rub to remain awake, and was able to follow simple, one-step commands. There were cranial nerve abnormalities, but a mild left pronation drift was noted. Overall, an unchanged examination from presentation. While in the operating room, a left subclavian central line and radial arterial line were placed along with a right external ventricular drain. On posthemorrhage day 5 (postoperative day 4), she developed a fever with a temperature of 39°C.

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Why is controlling fever after brain injury important?

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Fever after brain injury independently worsens outcome. One of the important mechanisms is by exacerbating inflammatory cascades. Postinjury elevations in temperature have been shown to increase inflammatory processes, including elevations in proinflammatory cytokines, the increased accumulation of polymorphonuclear leukocytes in injured tissue.1 The hypothalamus is a key center for thermoregulation and damage to this structure can result in hyperthermia. Vascular and inflammatory cascades appear to be extremely sensitive to mild elevations in temperature following CNS injury.

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Several studies also suggest that one of the key impacts of fever is an increase in neuronal excitotoxicity. Elevations in temperature have been reported to increase neurotransmitter release, accelerate free-radical production, increase intracellular glutamate concentrations, and potentiate the sensitivity of neurons to excitotoxic injury.1 In an experimental microdialysis study of focal ischemia, glutamate release was significantly higher in hyperthermic than normothermic rats, indicating the importance of focal brain temperature on neurotransmitter release.2 Other investigators have observed increases in cellular depolarization in the ischemic penumbra surrounding damaged neuronal tissue, increased neural intracellular acidosis, and inhibition of enzymatic protein kinases, which are responsible for synaptic transmission and cytoskeletal function in relation to elevations in core body temperature.3 At the molecular level, elevations in temperature have been shown to enhance the expression of heat-shock proteins, as well as receptor expression associated with glutamate neurotransmission.4

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Experimental and clinical studies have suggested that fever can also directly induce nervous system injury.5 In these circumstances, it is usually a temperature higher than 40°C for extended periods that produces abnormalities in the blood-brain barrier, as well as profound cardiovascular, metabolic, and hemodynamic dysfunction. Thus, mechanisms underlying hyperthermia-induced pathophysiology and secondary hyperthermia following central nervous system (CNS) injury are similar.

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A recent meta-analysis of all brain injury types found that fever is related to morbidity and mortality.6 However, several important questions regarding the impact timing and duration of fever on outcome remain unanswered. Is it the fever seen within the first 24 hours or within the first 10 days the most influential on outcome? Which is more important in influencing outcome: the number of febrile episodes or the overall burden of temperatures above 37°C in the first week? Both ...

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