Fever and brain injury

Elevation of body temperature occurring as a result of hypothalamic coordination of autonomic, neuroendocrine, and behavioral responses in reaction to physiological injury or invasion is generally known as fever. Traditional thought is that the “febrile response” is beneficial in preventing the proliferation of invading microorganisms, but some caregivers consider fever to be harmful and prescribe antipyretic agents and/or physical cooling methods to suppress fever. In their recent publication, Aiyagari and Diringer summarize the data that exists concerning the efficacy of physical and pharmacological treatments in reducing temperature and improving outcome in a variety of acute neurological disorders including stroke, traumatic brain injury, and cardiac arrest.

Several rationales exist for treating fever, including the relief of discomfort associated with fever, reduction of fever-imposed increase in metabolic demand, reduction in morbidity and mortality, reduction of fever-induced cognitive impairment, and prevention of febrile seizures. Most of these rationales are beneficial in theory, but have not been proven in practice. In the case of morbidity/mortality reduction, treatment with antipyretics has been shown to prolong certain infections; similarly, fever is known to improve survival of patients with community acquired pneumonia, Eschericia coli bacteremia, and Pseudomonas aeruginosa sepsis. Compounding these issues is the fact that traditional methods of lowering temperature in febrile patients are ineffective.

Elevated temperature exacerbates neuronal injury caused by cerebral ischemia or traumatic brain injury (TBI) and, conversely, hypothermia acts as a neuroprotectant in such cases. Well-controlled animal models of global and focal ischemia demonstrate a significantly detrimental effect of hyperthermia on clinical outcome and neuropathological changes. Ginsberg and Busto ( 1998 ) list a number of mechanisms through which hyperthermia worsens outcome in cerebral ischemia: increased neurotransmitter release, increased free radical production, opening of the blood-brain barrier, increased depolarizations within the penumbra, impaired brain metabolism and second messenger inhibition, and cytoskeletal degradation. The authors also note that “the action of otherwise neuroprotective drugs in ischemia may be nullified by mild hyperthermia.” Meticulous brain temperature monitoring and treatment of elevated temperature in patients suffering from neurological insult may, therefore, help prevent secondary injury.

Clinical studies of TBI and survivors of cardiac arrest have demonstrated an independent relationship between fever and poor outcome. Although fever is extremely common in neurological intensive care unit patients, the lack of effective fever treatment options has severely limited the availability of data regarding the benefits of fever reduction in such patients. However, recent advances in surface and intravascular cooling devices have lead to improvements in ability to reduce temperature, especially in patients with neurological injuries. An external cooling device known as the Medivance Arctic Sun temperature management system appears to be quite effective at reducing temperature in febrile patients (75% reduction in fever burden) as compared with more traditional means of fever reduction such as air- or water-circulating cooling blankets. Similarly, a newly-devised catheter-based heat exchange system (Cool Line/Cool Gard) has been tested in patients with subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), cerebral infarction, or TBI, showing a 64% reduction in fever burden as compared to the conventional treatment group (antipyretic, cooling blanket, and ice packs). Unfortunately, no data exists concerning these interventions’ impact on outcome.

As cooling devices and methods are improved and proven to be effective, more data concerning the effect of fever reduction on outcome should be forthcoming. Importantly, as Aiyagari and Diringer point out in the conclusion of their review:

“In the absence of conclusive data, the approach to fever management should be based on the balance between the potential for fever to exacerbate brain insults vs. enhance the ability to fight infections. Fortunately, the risk of ongoing brain injury is usually limited to the early phase in the course of most acute insults while the risk of infection rises as time goes on. Thus it would seem reasonable to aggressively control fever during the first few hours to days following ischemic stroke, intracerebral hemorrhage and head injury. Subsequently, aggressive fever control is less likely to be of help and could be detrimental.”

In cryonics patients, infection exacerbation is less important than protecting the brain from injury and warrants immediate induction of rapid cooling to protect patients from injury due to elevated temperatures. The benefits of treating fever in brain injury also highlights the importance of maintaining normothermia, or even hypothermia, in agonal (hypoxic) patients that present for cryopreservation.