What is it good for?


Something?  Maybe?  Remember in medical school when the right answer to everything was cytokines.  The mythical inflammatory response; all those interleukins, TNFs, and all other forms of molecular magic that drive our response to infection.  The so-called “pyrogens,” or molecular agents causing fever, are fundamental to the way we’ve evolved to fight infection.  And yet, as with so many disease processes, the offending agent may not be as much to blame as the cascade of pathophysiology.


The value of a febrile response is not a new debate, but it does seem have to lost its shine of late.  We’re pretty sure that we know much more than we used to.  And yet, we also know, from looking backwards, that so much of what we know “for sure” is bunk. Tomorrow, when your nurse informs you of that febrile rectal temp, (s)he expects the antipyretic and you want to give it. It’s just Tylenol after all. It’s what we do.


We have strong rationale.  When you suffered fever, you wanted it gone.   It feels crappy and it’s metabolically expensive.  On the micro level, it rev’s cells up, consumes more oxygen, spins those catabolic cycles, is pro-inflammatory.   On the macro level, it increases minute ventilation, and heart rate.  We know it’s bad for the injured-brain.  We even use response to fever-lowering agents as a diagnostic tool.  How does your febrile kid’s heart and respiratory rates respond to antipyretic?   (Meanwhile, no guidelines mention the response of vital signs to fever-lowering agents as a predictor of serious bacterial infection in kids.)


Fever ≠ hyperthermia.   Fever is an above-normal core temperature caused by an elevation of the set-point in the hypothalamus.  The body regulates temperature around this set point by balancing ambient temps, heat production and heat dissipation.  Hyperthermia happens when the set point remains normal, but there’s an imbalance in one of the above.


And it’s not just microbes that cause it; fever can be observed in trauma, CNS insults, malignancy, rheumatologic diseases, drug reactions, venous-thromboembolic disease, and toxins.  The etiologies of fever are many.  Do they all need to knocked down to normothermia?  We weren’t always so sure…


Hippocrates used “pyrotherapy” to treat mental illness.   “Pyrotherapy” was historically used in the treatment of polio and gonorrhea.  The 1927 Nobel Prize for physiology and medicine was given to Julius Wagner-Jauregg for his work championing induced-malaria fever as a treatment for neurosyphillis.   A gentleman and a scholar, he also advocated for castration as a treatment for schizophrenia and as a means to control the “lesser races.”  He was a Nazi.


So maybe it is good for something?  What’s the data?


There’s an ocean of animal data out there.  Did you know that cold-blooded creatures mount fevers by changing their behavior?  They get sick and go get more sun!   They’ve done studies in lizards, snakes, and fish showing that after injecting them with bacteria they become febrile; that the degree to which they mount a febrile response is associated with increased survival; and that antipyretics blunt the ability to mount fever and decrease survival.  In rabbits, they found that higher fevers had a kind of dose-dependent effect on decreasing survival (Kluger and Vaughn, 1978).


And what about us?  Made in God’s image.  Are we any different?  What’s the data?


In 1997, the Lancet published a randomized, not blinded, study of acetaminophen and/or external-cooling on children infected with malaria.  They found that parasite clearance time was longer for those who were cooled or given antipyretic.  Why they chose that outcome as opposed to a more clinical outcome isn’t clear.  But the findings make sense.  Historical docs used malaria to induce high fevers in an attempt to defeat a less treatable infection


Climbing the pyramid of evidence, in June 2013, The Journal of Critical Care published a systematic review and meta-analysis of antipyresis in the critically-ill, but not neurologically-injured, patient.  (Nivet et al, 2013)  They included 5 RCTs of antipyretics and fever.  For all-comers, there was no difference in mortality between those given antipyretic vs control.  The included trials were small and demonstrated no mortality benefit to those septic patients given ibuprofen.  In their meta-analysis, they included only 399 total patients.


Climbing back down the pyramid, a group in Australia/New Zealand did a retrospective, multicenter review of ~270,000 patients admitted to ICUs and looked for an association between temperature with mortality, in those with infection and those without. (Young et al, 2012) For those with infection, the lowest risk of death was in the group with a temp between 102 and 103 degrees F.   It was adjusted for disease severity.


The FACE group (Fever and Antipyretics in Critically Ill Patients Evaluation) recently published a large, observational study of 1,500 ICU patients, with and without infection. (Lee et al, 2012) They found a significantly increased risk of death for those septic patients treated with antipyretics.   The same did not hold true for non-infected patients.


Just food for thought.  There are no current RCTs on the efficacy and safety of acetaminophen in the critically ill septic patient.  The HEAT trial is active down under.  Check it:  www.heat-trial.org.nz


I hear you.  You’re saying that the critically-ill represent only a slice of what we see as EPs.   What about all those viral sydromes and febrile illnesses we diagnose?  Can’t we still throw motrin around the peds ED waiting room?


There’s this nice little randomized, placebo-controlled trial of acetaminophen in kids aged 6 months to 6 years with what looked like uncomplicated viral syndromes (Kramer et al, 1991).  They had parents give acetaminophen or placebo every four hours and record temps and rate their symptoms.  Those given APAP had better scores for “activity level” and “alertness.”  There was no difference in mood, comfort, appetite, or fluid intake.  There were no bad outcomes.  At the end, they asked the parents to guess whether their kid has received drug or placebo.  Both groups got it right close to 50% of the time.


Good or bad? Sepsis or simple viral syndrome?  The final word on antipyretics and infection isn’t in just yet.  But, it makes you wonder:  why something that is so metabolically expensive is conserved across the animal kingdom.  It seems like evolution has a shine for fevers….

















Daniel J. Niven, H. Tom Stelfox, Kevin B. Laupland, Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis, Journal of Critical Care, Volume 28, Issue 3, June 2013, Pages 303-310


Young PJ, Saxena M, Beasley R, et al. Early peak temperature and

mortality in critically ill patients with or without infection. Intensive

Care Med 2012;38:437-44


Lee BH, Inui D, Suh GY, et al. Association of body temperature and

antipyretic treatments with mortality of critically ill patients with and

without sepsis: multi-centered prospective observational study. Crit

Care 2012;16:R33


Wagner-Jauregg J (1927) The treatment of dementia paralytica by malaria innoculation Nobel Lectures:  Physiology or Medicine 1922-1941. Elsevier, New York, pp. 159-16



Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest N Engl J Med 2002, 346:549-556.



M.S. Kramer, L.E. Naimark, R. Roberts-Bräuer, A. McDougall, D.G. Leduc, Risks and benefits of paracetamol antipyresis in young children with fever of presumed viral origin, The Lancet, Volume 337, Issue 8741, 9 March 1991, Pages 591-594


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Jay Khadpe MD

  • Editor in Chief of "The Original Kings of County"
  • Assistant Professor of Emergency Medicine
  • Assistant Residency Director
  • SUNY Downstate / Kings County Hospital

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1 comment for “Fever…Huh

  1. Ian deSouza
    October 15, 2013 at 2:04 am

    Very interesting, Freedman. Nice work.

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