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  • Writer's pictureP.K. Peterson

Should Sepsis-related Fever Be Treated?

“Although high fever (>39.5C [103.1F]) control is usually performed in critically ill patients, available cohorts and randomized controlled trials do not support its use to improve sepsis prognosis.”

Marc Doman, et al, Frontiers in Medicine, October 2023


“Not too hot, not too cold, just right.”

James Kasting, American geoscientist (coining the term the “Goldilocks zone”)

 


In last week’s Germ Gems post, “Sepsis in Children: Recent Developments,” I emphasized the national and international efforts to increase early recognition of sepsis—a life-threatening disorder triggered by an over-reactive immune response to infection. In this week’s post, I focus specifically on the treatment of one of the cardinal symptoms and signs of sepsis, namely, fever.

Recap of fever. Fever, or pyrexia, is defined as an elevation of body temperature above a 'set-point' regulated by the body's thermoregulatory center (or thermostat) in the anterior hypothalamus of the brain. Cytokines released from activated immune cells are responsible for turning up the brain’s thermostat. A body temperature over 97.5F (36.6C)—not 98.6F (37C) as many of us were taught— is considered elevated in an adult.


Fever is an elegant host defense mechanism against foreign invaders like microbes. Some aspects of human immunity are enhanced at higher temperatures, and some pathogens just can’t stand the heat. Therefore, developing a fever is generally a good thing; it means your body’s immune system is doing its job.


In my January 4, 2023 Germ Gems article, “Fever Is Your Friend,” I made the case for not treating fever with antipyretic drugs or other measures that reduce body temperature. The basis for this argument is the pathophysiology of fever. A similar line of reasoning was laid out in a November 2020 article in Evolution, Medicine, and Public Health, “Let fever do its job.”


But fever must be distinguished from hyperthermia. Hyperthermia is an abnormally high body temperature resulting from exposure to high ambient temperatures, excessive physical activity, or certain medical conditions. Hyperthermia can lead to heat-related illnesses, such as heat exhaustion or deadly heat stroke. It is potentially lethal and should be considered a medical emergency.

What about fever in sepsis? Sepsis is the third most common cause of morality in hospitalized patients and, as some of us were surprised to learn last week, is the leading cause of death in children worldwide. Given the startling mortality of sepsis, it’s not surprising that some physicians, especially those working in intensive care units, have reconsideredtargeting one of the prominent symptoms and signs of sepsis—fever. (The other symptoms/signs of sepsis are tachycardia [rapid heart rate], shortness of breath, and confusion or disorientation.)


Clinicians working in the setting of intensive care units (intensivists) have raised the question of whether fever occurring in the context of sepsis should be treated be it with an anti-pyretic agent, such as one of the non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, naproxen, or indomethacin), or with the medicine acetaminophen (Tylenol or Paracetamol), or by using a cooling blanket. Their rationale and the results of randomized trials are discussed in “Temperature control in sepsis,” a mini review article published in Frontiers in Medicine in October 2023.


According to the authors, the clinical trials to date do not support the use of these treatment modalities to lower temperatures in patients with sepsis-related fever. For unclear reasons, they, nonetheless, suggest treating patients with very high temperatures (greater than 39.5C [103.1F]) with paracetamol or by cooling. The assessment of an ongoing trial using external cooling in mechanically ventilated patients with septic shock (SEPSISCOOL II) is pending completion of the study.


In addition to sepsis, the question of whether to treat fever has arisen from studies of COVID-19 patients. In an August 2023 article in Scientific Reports, “Body temperature as a predictor of mortality in COVID-19,” the authors of this retrospective study of over 10,000 in-patients observed that maximum body temperatures greater than 41C (105.8F) are an independent risk factor for a high mortality. But whether active management of body temperature was beneficial in reducing mortality was not assessed.


So what is an adult with a fever supposed to do? Fever is a tip-off that something’s wrong, most often an infection of some kind. Finding the cause of a fever is the first step in management.

When you develop a fever, it is the job of your health care provider to determine the diagnosis. If it is a “bacterial infection,” an appropriate antibiotic is prescribed. While antiviral drugs aren’t as readily available, if you’re infected by SARS-CoV-2, an antiviral agent for COVID-19 is in order. Additional therapeutic measures, which generally don’t include an antipyretic, will depend upon the diagnosis.  And, if it’s not clear what is going on, your primary care provider may consult an infectious diseases specialist, who spends a good deal of their professional time puzzling about fevers.


As a general rule, however, a fever indicates that Mother Nature is pulling for you; your immune system is working.  Sometimes it’s best to just let Mother Nature do her job.

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Main Page images courtesy of Shuxian Hu, MD. Dr. Hu is a scientist in the Neuroimmunology Research Laboratory at the University of Minnesota.

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