Should We Reconsider Antipyretics For Fever?

What is Fever?

Although often used interchangeably, the terms fever and hyperthermia refer to different processes, and the distinction is key. In fever the thermoregulatory set-point is elevated, and the body actively raises its temperature with chills and rigors to reach the new set-point. In hyperthermia the body’s temperature exceeds the set-point, due to increased heat production (eg hypermetabolic state) or decreased dissipation (eg high humidity or ambient temperature).1

Fever is generally defined as temperature ≥38°C (100.4°F) and results from a complex mechanism. The body produces pyrogens (specific cytokines) that act on the thermoregulatory center in the hypothalamus to increase the set-point. This is thought to occur by increased prostaglandin synthesis, and antipyretic drugs lower the set-point likely by inhibiting prostaglandin synthesis.2 There are also numerous endogenous antipyretics (cryogens).

Increased temperatures enhance immune function in many ways, including improved neutrophil migration and secretion of antibacterial substances, increased interferon, and increased T cell proliferation.1

2

Fever Anxiety

A 1980 study titled “Fever phobia: misconceptions of parents about fever” surveyed parents, and found 94% thought fever may have harmful effects, 18% thought brain damage or serious harm could result from fever <38.9°C (102°F), and 16% thought fever could rise up to 48.9°C (120°F) if untreated.3 A 2001 study re-examined similar questions, and found 76% believed serious harm could occur at ≤40°C (104°F).3

This phobia also exists among healthcare workers. A 1992 survey by the American Academy of Pediatrics in Massachusetts showed 65% of pediatricians thought fever alone is potentially dangerous, 72% “always or often” prescribed antipyretics for fever, and 89% recommended antipyretics for fever of 101-102°F.4 A 2000 study of pediatric emergency department nurses, with a median experience of 8 years, found 11% were unsure what temperature constituted fever, 29% thought permanent brain injury or death could occur from high fever, and 18% believed it is dangerous for children to be discharged from the emergency department if still febrile.5

Is Fever Harmful?

Some providers have concerns that the increased temperature or metabolic demand from fever will harm patients. Humans generally tolerate temperatures below 41°C (105.8F) without harm. In contrast to hyperthermia, it is extremely rare for fever as a host defense against infection to reach dangerous temperatures in neurologically normal patients, since the body is actively adjusting both the set-point and actual temperature.3 A 2011 American Academy of Pediatrics policy paper states “There is no evidence that fever itself worsens the course of an illness or that it causes long-term neurologic complications.” 6

Pediatric febrile seizures are associated with fever, but there is no evidence that simple febrile seizures have long-term consequences. One study of 431 sibling pairs, in which only one had a febrile seizure, found no difference in subsequent intelligence, behavior, or academic performance.7 There are multiple well powered studies on motor and cognitive function after febrile seizures, and even after prolonged febrile seizures the incidence of morbidity is extremely low.

Benefits of Fever

Dr. Sydenham (a father of English medicine, of Sydenham’s chorea) in 1666 wrote that “fever is nature’s engine which she brings into the field to remove her enemy.” This positive view of the febrile response was the norm, shared by Hippocrates, American Indian tribes, and almost everyone in between, but started to change in the late 19th century, when antipyretics became widely available.1 Studies on the role of fever fall into 4 categories: 1) evolutionary, 2) correlational, 3) hyper/hypothermia, and 4) antipyretic.

Evolutionary: The febrile response after injection of pyrogens (eg endotoxin) is conserved across endothermic and ectothermic animals, with very few exceptions. Since this requires an increase in precious metabolic energy, the preservation of such a complex mechanism across the animal world points toward an evolutionary advantage of the febrile response.

Correlational: In one study, ferrets’ nasal passages were inoculated with a standardized amount of influenza virus, and those that mounted a higher fever subsequently had fewer live viruses able to be cultured back from the nasal passages. Ectothermic species such as lizards preferentially choose a warmer ambient temperature when infected, which has been shown to improve survival.1

Hyperthermia: Studies suggest higher temperatures are beneficial in infection. Dogs exposed to canine herpesvirus did better in higher ambient temperatures, and mice infected with rabies had increased survival in higher ambient temperatures.1

Hypothermia: These studies are slightly more varied in their conclusions. Of 21 animal studies that investigated cooling during infection, 7 found a protective effect and 14 found increased harm. Although the majority of animal cooling studies support that fever is beneficial, there do exist well conducted studies that do not support that conclusion.1

Antipyretic: Numerous animal studies show harm or increased viral/bacterial titers in animals treated with antipyretics. One RCT gave an NSAID to goats infected with a parasite, blocking the febrile response. 5/5 goats given the NSAID died, while 16/17 goats that did not get the NSAID had a mild infection.1

Human Studies

  • A 2005 study in a Trauma ICU randomized 82 febrile patients to aggressive or less aggressive treatment with antipyretics and cooling blankets based on temperature >38.5°C vs. >40°C, and the group that was more aggressively cooled had worse mortality.8
  • A 2012 prospective study of 737 febrile ICU patients found increased 28 day mortality when acetaminophen was given to septic patients, but not if the patient lacked sepsis.9
  • A 2013 meta-analysis of 5 RCT’s (399 patients), including the 2005 Trauma ICU study, found clinical equipoise. The trials were heterogenous, involving a mix of antipyretics and mechanical cooling, and the pooled risk ratio’s confidence interval ranged from significantly increased to significantly reduced mortality.10
  • The 2015 HEAT trial published in NEJM randomized 700 febrile ICU patients to receive regular acetaminophen IV vs. placebo. It found no difference in ICU free days (primary outcome), or in 28 or 90 day mortality.11
  • An RCT from New Zealand published this month (Feb 2016) investigating regular acetaminophen vs. placebo for influenza found no difference in fever, viral shedding, or symptoms, but it was under-powered and had other significant limitations.12

Treatment Rationale

The primary reason to treat fever with antipyretics is to reduce discomfort. One controlled study of acetaminophen vs. placebo asked parents to rate their febrile children, and found improved activity, mood, and appetite with acetaminophen though no change in fever duration. A separate controlled study in which febrile children rated their own discomfort demonstrated marked improvement with ibuprofen vs. placebo.13

The British National Institute for Health and Care Excellence (NICE) guidelines for febrile children under 5 years recommend considering antipyretics if they “appear distressed,” but “do not use antipyretic agents with the sole aim of reducing body temperature in children with fever.”14

The other reason to consider treating fever is concern for febrile status epilepticus in children, since it can potentially cause brain damage. However, multiple RCT’s have found no short or long-term reduction in recurrent febrile seizures with antipyretics, and antipyretics to prevent simple febrile seizures are not routinely indicated.15 The American Academy of Pediatrics 2008 Practice Parameter is in agreement.

Provider Role

In both the 1980 and 1999 surveys described above, patients and families considered doctors and nurses the most important sources of information on fever. Discharge instructions often recommend calling or returning if a fever rises above a certain point (usually arbitrary), or persists for a certain amount of time (also usually arbitrary). Many providers never discuss with patients and families the definition of fever, or its potential benefits. As Crocetti et al. eloquently wrote, “By placing emphasis on knowing a child’s temperature and concurrently giving inadequate information about fever, one may heighten anxiety and perpetuate fever phobia.”3

Take Home Points

Always distinguish between fever as a host response and hyperthermia. Based on current literature, a reasonable approach is to treat fever with antipyretics if the patient is uncomfortable, or on a case-by-case basis if there is specific concern for febrile status epilepticus in children. If a patient appears relatively comfortable despite a fever, you can safely reconsider routine antipyretics.

The data is fairly heterogeneous, and consider that your patient may not share characteristics with the study populations, or you may be interested in a specific outcome that was not investigated. However, based on current evidence, there is generally no demonstrated benefit to normalizing a febrile patient’s temperature, and there is some weak evidence that it may even be harmful.

Providers should not view an elevated temperature as an independent contraindication to discharge home. For patients with fever (even if only diagnosed clinically) who are discharged home, it should generally be emphasized in return and follow-up precautions to focus on signs and symptoms rather than specific temperatures.

1

Resident Review: Dr. Eddie Ruhland
Faculty Review: Dr. Gita Pensa

References

  • Kluger, M.J., et al. (1996). The adaptive value of fever. Infectious disease clinics of North America, 10(1), 1-20.
  • Adam, H.M. (2013). Fever: measuring and managing. Pediatrics in review, 34(8), 368-70.
  • Crocetti, M., Moghbeli, N., Serwint, J. (2001). Fever phobia revisited: have parental misconceptions about fever changed in 20 years?. Pediatrics, 107(6), 1241-1246.
  • May, A., Bauchner, H. (1992). Fever phobia: the pediatrician’s contribution. Pediatrics, 90(6), 851-854.
  • Poirier, M.P., et al. (2000). Pediatric emergency department nurses’ perspectives on fever in children. Pediatric emergency care, 16(1), 9-12.
  • Sullivan, J.E., Farrar, H.C. (2011). Fever and antipyretic use in children. Pediatrics, 127(3), 580-587.
  • Habbick, B.F. (1988). Fever in Children: Should it be Treated?. Canadian Family Physician, 34, 1161.
  • Schulman, C.I., et al. (2005). The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surgical infections, 6(4), 369-375.
  • Lee, B.H., et al. (2012). Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Critical Care, 16(1), 1-13.
  • Niven, D.J., et al. (2013). Antipyretic therapy in febrile critically ill adults: a systematic review and meta-analysis. Journal of critical care, 28(3), 303-310.
  • Young, P., et al. (2015). Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. New England Journal of Medicine, 373(23), 2215-2224.
  • Jefferies, S., et al. (2016). Randomized controlled trial of the effect of regular paracetamol on influenza infection. Respirology.
  • Knoebel, E.E., Narang, A.S., Ey, J.L. (2002). Fever: To treat or not to treat. Clinical pediatrics, 41(1), 9.
  • National Institute for Health and Care Excellence (NICE). (2013). Fever in under 5s: assessment and initial management [CG160]. http://www.nice.org.uk/guidance/cg160.
  • Lux, A.L. (2010). Treatment of febrile seizures: historical perspective, current opinions, and potential future directions. Brain and Development, 32(1), 42-50.

2 thoughts on “Should We Reconsider Antipyretics For Fever?

  1. great job, interesting topic. The literature is pretty darn clear and has been for years, that fever up to a point is beneficial in an infection. What that point is, is also argued about, but many have (arbitrarily?) chosen 103.5. It’s just that temps over 101 make most people feel miserable, and crying children make parents and docs want to DO something. Just say no!

  2. Pingback: Urine herpes test – STDs – MedHelp | Herpes Survival Kit

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