Fever control and its impact on outcomes: What is the evidence?

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Abstract

Fever is common in a variety of neurological disorders. There is abundant experimental evidence suggesting that fever leads to, or exacerbates, neuronal injury in conditions such as cerebral ischemia and traumatic brain injury. However, conclusive evidence linking control of fever to improved outcomes is lacking. It has been difficult to design studies looking at the impact of fever control on outcome, in part because traditional methods of fever control are ineffective. Recently, several new devices to control temperature have become available. These devices appear to be more effective than conventional means and might allow us to design studies that definitively answer the question: “Does controlling fever improve outcome?”

Introduction

Fever is a stereotyped adaptive response to a variety of infectious and other inflammatory stimuli. It is the result of a complex interplay of neuroendocrine, autonomic and behavioral responses coordinated by the hypothalamus that leads to a variety of physiological perturbations, the most apparent of which is an elevation of body temperature [1]. Fever has been classically described as having three phases. In the first phase, there is cutaneous vasoconstriction and diversion of blood from the surface to the core of the body. Muscles contract, leading to shivering, chills and excess heat production. This leads to the elevation of body temperature. In the second phase, heat production and heat loss are equal, and the body maintains an elevated temperature. In the third phase, cutaneous vasodilation and sweating lead to a loss of excess heat, and body temperature is lowered to normal. The “febrile response” is thought to confer an immunological advantage to the host over invading microorganisms. Therefore, the value of routinely lowering elevated temperature in febrile patients by physical or pharmacological means has been questioned [2]. Nonetheless, many patients and caregivers consider fever to be harmful and it has been estimated that 70% of nurses and 30% of physicians routinely use antipyretic agents to suppress fever [3]. In this article we summarize the data concerning the risks and benefits of treating fever and critically evaluate the evidence in support of improved outcomes with control of fever, specifically in patients with neurological and neurosurgical disorders such as stroke, traumatic brain injury (TBI) and survivors of cardiac arrest (CA).

Section snippets

Relief of discomfort

The febrile state is unpleasant and antipyretics are commonly employed to enhance patient comfort. The degree of relief provided by antipyretics, however, has never been quantified in well designed studies. Several studies of external cooling have shown that despite reduction of temperature, patient discomfort might actually increase [4], [5], [6]. In contrast, a recent study showed that discomfort was eased with fall in temperature but was not related to the magnitude of fever. In addition,

Fever and brain injury

There is abundant evidence from animal experiments and clinical studies suggesting that elevated temperature exacerbates neuronal injury in the setting of TBI and focal or global cerebral ischemia. The mechanisms by which hyperthermia mediates neuronal injury have been reviewed by Ginsburg and Busto [21]. A wealth of animal studies also supports the hypothesis that hypothermia has a neuroprotectant effect. Recently, two large, randomized, double-blind placebo controlled trials have shown that

Treatment of fever in the setting of neurological injury

Clinicians have been treating fever using external cooling methods and antipyretic drugs for over 2000 years. Yet, data about the efficacy of physical methods and pharmacological agents in reducing temperature and improving outcomes is quite sparse, especially in the adult population. Recently, newer surface and intravascular cooling devices have been introduced which seem to be more effective in reducing temperature compared to the more traditional methods, especially in patients with

Conclusion

Although there is a body of experimental data and clinical experience that relate fever to more substantial neurologic injury and worse outcome, the answer to the critical question: “Does fever control improve outcome?” is not known. This is not to indicate that absence of proof is proof of absence. The definitive study has not been performed. This has been in large part due to the lack of an effective means to control fever, although effective means may now be at hand.

In the absence of

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