Everything we do in medicine is nuanced. We have different methods of treating patients with abnormal vital signs, based on the etiology of their disease. For example, we don't give everyone with hypotension a fluid bolus; they may have an ejection fraction of 15%, they may have a hemoglobin of 5, they may be septic, or have accidentally overdosed on their blood pressure medications. The point is, for one abnormal vital sign, there are countless causes, and treatments vary from patient to patient. Given the current body of evidence, our interventions are often tailored toward what is deemed the most beneficial for the patient.
Although we have the best intentions, treating fevers in certain patient populations may not be optimizing their care and could inadvertently be causing harm.
Why is This Education Targeted Towards Nurses?
According to PhD RN Hilaire Thompson (2012), bedside nurses are the primary decision makers for implementing fever management interventions, and we often use a what works philosophy rather than evidence-based practice in our decision making. As nurses, it is our job to escalate abnormal vital signs to providers and to advocate for our patients. In doing so, we often advocate for temperature control measures such as acetaminophen when we notice even the slightest deviation from baseline regarding temperature. Not only that, but we also cool rooms for patients when we deem it best, we implement ice packs without orders, place cool washcloths on their foreheads, fan patients, and often ask to escalate to cooling blankets for temperature treatment. Sometimes we do these interventions without orders. As I stated before, although we may believe we are doing what is best for the patient, we may unknowingly be negatively impacting their care.
What is Fever, and How is it Defined?
The textbook Critical Care Emergency Medicine states, Fever is an adaptation mechanism of the body in response to internal and external environmental stressors, and is a key indicator of immune system activation Fever occurs when cytokines cause an increase in body temperature in association with a rise in hypothalamic set point (Rosenthal, 2012). The set point that the Society of Critical Care Medicine (SCCM) and the Infectious Disease Society of America (IDSA) define as fever is a temperature exceeding 38.3 C (101F). These organizations have suggested 38.3 C as the threshold of fever for research & practice. Per Harvard Health (2023), 38.1-39 C (100.4-102.2F) is considered a moderate fever and a normal physiologic response to infection.
The SCCM and IDSA also include nuanced criteria for what is considered fever among geriatric patients, immunocompromised individuals, traumatic brain injury, and subarachnoid hemorrhage, and detail infectious vs. noninfectious causes of fever. All of this suggests that a more nuanced approach to temperature management ought to be considered in special populations, while the majority of fever occurs secondary to infectious etiologies.
A Very Brief History of Pyrexia:
Fever serves as a crucial physiological response to infection, a mechanism that has persisted across warm-blooded and cold-blooded vertebrates for more than 600 million years of evolutionary history. Elevated body temperatures are inherently linked to the inflammatory response, with heat (calor) recognized as one of the four key indicators of inflammation, a concept originally outlined in 30 BCE. The continued presence of fever throughout vertebrate evolution strongly indicates that elevated temperatures confer a significant survival advantage (Evans et al., 2015).
Infectious Mechanism of Fever:
Analysis of over 1000 hospital studies shows that infection is the origin of between 37-74% of febrile patients who present to the hospital (Kaul et al., 2006). The mechanism of fever involves an initial biological insult to the body (infectious pathogen)- macrophages ingest said exogenous pathogens, and release endogenous pyrogenic cytokines and proinflammatory cytokines (IL-1, IL-6, TNF-alpha, & type I interferons) to illicit adaptive immune activation and improve presentation to CD8+ T cells. These cytokines inevitably circulate to the brain, and these pyrogens stimulate the release of Prostaglandin E2 (PGE2). PGE2 interacts with the hypothalamus and increases the body's set temperature point (which can be regulated up to 42 C) to aid in the fight against infection (Balli et al., 2023; Walter et al., 2016). The hypothalamus uses the neuroendocrine effector arm to regulate behavior to generate heat (increased muscle tone, shivering, thyroxine production to increase metabolism, catecholamine and glucocorticoid release) and prevent heat loss (cutaneous vasoconstriction [AV shunts] to centralize heat) to mount a fever and thus prevent the spread of infection (Schell-Chaple, 2024).
Temperature elevation enhances immune response, inhibits bacterial growth and viral replication, stimulates phagocytosis, and increases the speed of white blood cell (WBC) production through pathways I will discuss below.
When the body's temperature exceeds 38 C, it upregulates production of interferons (IFN) alpha, beta, and gamma as well as both proinflammatory cytokines IL-1, IL-6, and proinflammatory transcription factor NF-KB and STAT3 (Balli et al., 2023; Rummel, 2015). IL-1 is more active in febrile states, and interferons (IFN) are a group of intrinsic antiviral agents that exhibit increased antiviral effectiveness at temperatures above 40 C. (EL-Radhi, 2012). These factors act in a paracrine-like way, where signals travel from cell to cell, and warn each other to downregulate receptors that would allow pathogen entry into the cell. Thus, fever serves as a protective mechanism to halt pathogen proliferation.
Temperatures ranging from 38 to 39 C have been shown to exert a direct positive influence on lymphocyte differentiation, the formation of cytolytic (NK) cells, B-cell activity, and the synthesis of immunoglobulins. Additionally, the cross-presentation of antigens on dendritic cells and macrophages to CD8+ T cells is enhanced within this temperature range (Wrotek et al., 2020).
Temperature ranges between 40 C and 41 C have been shown to induce a 200-fold reduction in the replication rate of polio virus and increase the susceptibility of Gram-negative bacteria to lysis. Through cytokine release (from fever), we can more efficiently target pathogens and direct adaptive immune lymphocyte development (Evans et al., 2015).
How many nurses or doctors are comfortable letting a patient reach core body temperatures up to 42 C (107.6 F)? Not very many, however, there is no evidence of patients having their brains fried or proteins denatured at this temperature, in large part due to the presence of Heat Shock Proteins (HSP), which are activated at temperatures of 38 C and above, but are most expressed at temperatures of 41 C and above. HSP family proteins serve many functions, including acting as chaperone proteins, preventing the misfolding of our host proteins while not protecting viral or bacterial proteins, further decreasing their ability to replicate and survive in vivo (Lauber et al., 2015).
Why Our Current System May Be Suboptimal
Since fevers indicate inflammation, fever resolution can be an important clinical tool to measure how the body is responding to treatments such as antibiotics. However, with fever reducers such as acetaminophen, we lose this important clinical marker with induced normothermia.
Benefits of Allowing Fever?
Temperature elevation enhances immune response, inhibits bacterial growth and viral replication, stimulates phagocytosis, and increases the speed of WBC production (Schell-Chaple, 2024).
The use of antipyretic drugs to diminish fever correlates with a 5% increase in mortality in human populations infected with the influenza virus and negatively affects patient outcomes in the intensive care unit (Earn et al., 2014; Ryan & Levy, 2003). Schulman et al. (2005) showed increased mortality with treating fevers in a trauma ICU.
Additional studies on fever and fever management in the hospital
1. Fever in the Emergency Department Predicts Survival of Patients with Severe Sepsis and Septic Shock Admitted to the ICU (Sunden-Cullberg et al, 2017)
Aim: To study the prognostic value of fever in the ED in septic patients requiring ICU care
- Observational cohort, 30 ICUs, n = 2,225 adults
- Primary outcome: in-hospital mortality
Results
- 45% with fever (>38.3 C), 55% with low or normal body temp (< 38.3 C/100.9F), 23% < 37 C
- Among vital signs, Body Temp was the best predictor of mortality
- If febrile, better Quality of care(more prompt ABx admin)
- Lowest mortality in febrile patients
- The lower the core body temperature, the higher the mortality rate
2. Fever is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials (Rumbus et al., 2017)
- Meta-analysis of clinical trials: 42 studies (n = 10,834)
Aim: To study the association between Body temperature and mortality in septic patients
Results
- Compared to normothermia, fever is associated with lower mortality, and hypothermia is associated with higher mortality
Mortality based on Body Temperature Groups
- Hypothermia 47.3%
- Normothermia 31.2%
- Fever (>38C) 22.2%
3. Body Temperature and Mortality in Patients with Acute Respiratory Distress Syndrome (Schell-Chaple et al, 2015)
ARDS patients (n=969): Etiology of ARDS was Infection: 71% (Pneumonia: 67%), & 33% were found to have severe Sepsis.
Results:
Baseline Body Temperature is independently associated with mortality
Mortality, OR 0.85 (95%CI .73-.98):
For every 1 C increase, mortality decreased 15%
Conclusion
In conclusion, fevers induce proinflammatory & proimmune responses. These intrinsic responses confer antibacterial, antiviral, and mortality-associated benefits. When regulated, fevers are generally not harmful and can be important indicators of response to treatments. Meta-analysis shows there is no harm in letting a fever run its course in critically ill patients with infection (Wrotek 2020) & we can still give acetaminophen for other reasons, such as for pain.
All in all, when it comes to critical patients, we need every tool in the toolbox to fight infection. Fever is one of the body's best defenses; as such, we should tailor the treatment of infection to allow for permissive pyrexia, or at the very least raise the threshold for treating fever for patients with acute infections and evaluate acetaminophen administration on a case-by-case basis. I believe abnormal vital signs should continue to be escalated to providers, but we as nurses shouldn't push for acetaminophen in certain patient populations, nor should we administer environmental cooling measures based on preference rather than best practice.
References:
Balli, S., Shumway, K. R., & Sharan, S. (2023, September 4). Physiology, fever. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK562334/
Earn, D. J. D., Andrews, P. W., & Bolker, B. M. (2014). Population-level effects of suppressing fever. Proceedings of the Royal Society B Biological Sciences, 281(1778), 20132570. https://doi.org/10.1098/rspb.2013.2570
El-Radhi, A. S. M. (2012). Fever management: Evidence versus current practice. World Journal of Clinical Pediatrics, 1(4), 29. https://doi.org/10.5409/wjcp.v1.i4.29
Evans, S. S., Repasky, E. A., & Fisher, D. T. (2015). Fever and the thermal regulation of immunity: the immune system feels the heat. Nature Reviews. Immunology, 15(6), 335349. https://doi.org/10.1038/nri3843
Harvard Health. (2023, May 22). Fever in adults: When to worry. https://www.health.harvard.edu/diseases-and-conditions/treating-fever-in-adults#:~:text=While%20any%20temperature%20above%20your,(39.1%20to%2041%20C).
Kaul, D. R., Flanders, S. A., Beck, J. M., & Saint, S. (2006). Brief report: Incidence, etiology, risk factors, and outcome of hospital-acquired fever: a systematic, evidence-based review. Journal of General Internal Medicine, 21(11), 11841187. https://doi.org/10.1111/j.1525-1497.2006.00566.x
Lauber, K., Brix, N., Ernst, A., Hennel, R., Krombach, J., Anders, H., & Belka, C. (2015). Targeting the heat shock response in combination with radiotherapy: Sensitizing cancer cells to irradiation-induced cell death and heating up their immunogenicity. Cancer Letters, 368(2), 209229. https://doi.org/10.1016/j.canlet.2015.02.047
Rosenthal, M. E. (2011). Critical Care Emergency Medicine, Chapter 34 (D. A. Farcy, W. C. Chiu, & J. P. Marshall, Eds.). The McGraw-Hill Companies. https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=522ionid=41291793
Rumbus, Z., Matics, R., Hegyi, P., Zsiboras, C., Szabo, I., Illes, A., Petervari, E., Balasko, M., Marta, K., Miko, A., Parniczky, A., Tenk, J., Rostas, I., Solymar, M., & Garami, A. (2017). Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials. PLoS ONE, 12(1), e0170152. https://doi.org/10.1371/journal.pone.0170152
Rummel, C. (2015). Inflammatory transcription factors as activation markers and functional readouts in immune-to-brain communication. Brain Behavior and Immunity, 54, 114. https://doi.org/10.1016/j.bbi.2015.09.003
Ryan, M., & Levy, M. M. (2003). Clinical review: fever in intensive care unit patients. Critical Care, 7(3), 221. https://doi.org/10.1186/cc1879
Schell-Chaple, H. M., Puntillo, K. A., Matthay, M. A., & Liu, K. D. (2015). Body Temperature and Mortality in Patients with Acute Respiratory Distress Syndrome. American Journal of Critical Care, 24(1), 1523. https://doi.org/10.4037/ajcc2015320
Schell-Chaple, H. (2024). Fever Management and Sepsis: Discovering the Evidence to Guide Nursing Practice - AACN. AACN. https://www.aacn.org/education/ce-activities/nti24246/fever-management-and-sepsis-discovering-the-evidence-to-guide-nursing-practice
Schulman, C. I., Namias, N., Doherty, J., Manning, R. J., Li, P., Elhaddad, A., Lasko, D., Amortegui, J., Dy, C. J., Dlugasch, L., Baracco, G., & Cohn, S. M. (2005). The Effect of Antipyretic Therapy upon Outcomes in Critically Ill Patients: A Randomized, Prospective Study. Surgical Infections, 6(4), 369375. https://doi.org/10.1089/sur.2005.6.369
Sundén-Cullberg, J., Rylance, R., Svefors, J., Norrby-Teglund, A., Björk, J., & Inghammar, M. (2017). Fever in the emergency department predicts survival of patients with severe sepsis and septic shock admitted to the ICU*. Critical Care Medicine, 45(4), 591599. https://doi.org/10.1097/ccm.0000000000002249
Thompson, H. J., & Kagan, S. H. (2010). Clinical management of fever by nurses: doing what works. Journal of Advanced Nursing, 67(2), 359370. https://doi.org/10.1111/j.1365-2648.2010.05506.x
Walter, E. J., Hanna-Jumma, S., Carraretto, M., & Forni, L. (2016). The pathophysiological basis and consequences of fever. Critical Care, 20(1). https://doi.org/10.1186/s13054-016-1375-5
Wrotek, S., LeGrand, E. K., Dzialuk, A., & Alcock, J. (2020). Let fever do its job. Evolution Medicine and Public Health, 9(1), 2635. https://doi.org/10.1093/emph/eoaa044
About the Author:
Matthew Gallagher, the winner of CEUfast's Undergraduate Scholarship, was inspired to pursue healthcare after experiencing a life-threatening cardiac event during college. His career path has included roles as a nutrition representative, EMT, phlebotomist, paramedic, and ER trauma tech before earning his nursing degree in 2021 and beginning work in the ICU. He is now advancing his education by pursuing a BSN, with plans to continue into a master's program.
Matthew is an independent contributor to CEUfast's Nursing Blog Program. Please note that the views, thoughts, and opinions expressed in this blog post are solely those of the independent contributor and do not necessarily represent those of CEUfast. This blog post is not medical advice. Always consult with your personal healthcare provider for any health-related questions or concerns.
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