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Fever, Friend or Foe?

Fever is so hot right now…

‘Humanity has but three great enemies: fever, famine and war; of these by far the greatest, by far the most terrible, is fever’— William Osler1

William Osler. The study of the Fevers of the South. JAMA 1896; 21: 999–1004

Fever is one of the cardinal signs of infection and — nearly 120 years after William Osler’s statement in his address to the 47th annual meeting of the American Medical Association on The Study of the Fevers of the South1 — infectious diseases remain a major cause of morbidity and mortality2. Despite this, it is unclear whether fever itself is truly the enemy or whether, in fact, the febrile response represents an important means to help the body fight infection. Furthermore, it is unclear whether the administration of antipyretic medications to patients with fever and infection is beneficial or harmful3,4.

The febrile response to infection is seen in a range of animal species including not only endotherms like mammals5-8 and birds9 but also ectotherms including reptiles10, amphibians11, and fish12. The febrile response in desert iguanas13 and bluegill sunfish14, like the response seen in humans, can be blocked by inhibition of cyclooxygenase (COX). As COX catalyses the generation of prostaglandins from arachidonic acid, this suggests that the pivotal role of PGE2 in the regulation of the thermostatic set point may be preserved in these species as well as in higher animals. A common biochemical mechanism regulating fever across such a diverse group of animals raises the possibility that the febrile response may have evolved in a common ancestor. If this is the case, then fever probably emerged as an evolutionary response more than 350 million years ago15.

As the febrile response comes at a significant metabolic cost16,17, its persistence across such a broad range of species provides strong circumstantial evidence that the response has some evolutionary advantage. Furthermore, given that the response appears ubiquitous it logically follows that the components of the immune system would have evolved to function optimally in the physiological febrile range.

There are a number of historical examples of dramatic responses to treatment with therapeutic hyperthermia in some infectious diseases. It has been known since the time of Hippocrates that episodes of ‘progressive paralysis’ due to neurosyphilis sometimes resolve after an illness associated with high fever. This observation led Julius Wagner-Jauregg to propose, in 1887, that inoculation of malaria might be a justifiable therapy for patients with ‘progressive paralysis’. His rationale was that one could substitute an untreatable condition for a treatable one – malaria being treatable with quinine. In 1917, he tested his hypothesis in nine patients with paralysis due to syphilis by injecting them with blood from patients suffering from malaria. Three of the patients had remission of their paralysis. This led to further experiments and clinical observations on more than a thousand patients where remission occurred in 30% of patients with neurosyphilis-related progressive paralysis ‘treated’ with fever induced by malaria compared to spontaneous remission rates of only 1%. This work on fever therapy led to Julius Wagner-Jauregg being awarded the Nobel Prize in Physiology or Medicine in 192718. Subsequently, fever therapy was shown to be effective in treating gonorrhoea. Inducing hyperthermia of 41.7°C for six hours with the Kettering hypertherm chamber led to cure in 81% of cases19.

The relevance of these historical examples to the modern era is unclear. Furthermore, arguments based on the evolutionary importance of the febrile response do not necessarily apply to critically ill patients who are, by definition, supported beyond the limits of normal physiological homeostasis. Humans are not adapted to critical illness. In the absence of modern medicine and Intensive Care, most critically ill patients with fever and infection would presumably die. Among critically ill patients, it seems likely that there is a balance to be struck between the potential benefits of reducing metabolic rate that come with fever control and the potential risks of a deleterious effect on host defence mechanisms. Where this balance lies is very uncertain as there are very few interventional studies of fever management in critically ill patients (see Table 1). Remarkably, although paracetamol is very widely used in ICU patients with fever and known or suspected infection, there are no randomised controlled trials of paracetamol in this patient population and the safety and efficacy of current clinical practice is uncertain. The efficacy and safety of administration of paracetamol to critically ill patients with fever and infection is currently being investigated in the HEAT trial (www.heat-trial.org.nz).

Table 1: Summary of randomised controlled trials investigating the management of fever in critically ill adults

123
DesignKey Findings
Bernard et al 1991 20Double blind placebo-controlled trial of ibuprofen in patients with severe sepsis; n = 30
  • Ibuprofen significantly reduced temperature, heart rate, and peak airway pressure
  • There was no significant difference between ibuprofen and placebo in terms of in-hospital mortality rate (18.8% ibuprofen-treated group vs. 42.9% placebo-treated group)
Bernard et al 1997 21Double blind placebo-controlled trial of ibuprofen in patients with severe sepsis in seven centres in North America; n=455
  • Ibuprofen significantly reduced temperature, heart rate, oxygen consumption, and lactic acidosis in patients with severe sepsis
  • Ibuprofen did not alter the incidence or duration of shock or ARDS and had no significant effect on 30-day mortality (37% ibuprofen-treated group vs. 40% placebo-treated group)
Memis et al 2004 22Double blind placebo-controlled trial of lornoxicam in patients with severe sepsis in one centre in Turkey; n=40
  • No significant difference between lornoxicam and placebo was demonstrated in terms of haemodynamic parameters, biochemical parameters, cytokine levels, or ICU mortality (35% lornoxicam-treated group vs. 40% placebo-treated group)
Morris et al 2011 23Multicentre, randomised trial comparing the antipyretic efficacy of a single dose of placebo, 100mg, 200mg, or 400mg of IV ibuprofen in hospitalised patients of whom >90% had infections; n=120 (53 critically ill)
  • All doses of ibuprofen tested were effective in lowering temperature.
  • There were no significant difference between treatment groups with respect to ventilation requirements, length of stay or in-hospital mortality (4% placebo, 3% 100mg ibuprofen, 7% 200mg ibuprofen, 6% 400mg ibuprofen)
Haupt et al 1991 24Multicentre, placebo-controlled randomised trial of ibuprofen in patients with severe sepsis; n=29
  • Ibuprofen significantly reduced body temperature
  • There was no significant difference between the treatment groups in terms of in-hospital mortality (30.8% in the placebo group vs. 56.3% in the ibuprofen group)
Schulman et al 2006 25Single centre, unblinded, randomised trial of aggressive vs. permissive temperature management in febrile patients in a trauma ICU; n=82
  • There was no significant difference between the treatment arm in terms of the number of new infections
  • The in-hospital mortality was 15.9% in the aggressive treatment group and 2.6% in the permissive treatment group (P=0.06)
Niven et al 2012 26Multicentre, unblinded randomised trial of aggressive vs. permissive temperature management in febrile ICU patients; n=26
  • The mean daily temperature was lower in the patients assigned to aggressive fever management
  • The in-hospital mortality was 21% in the aggressive treatment group and 17% in the permissive treatment group (P=1.0)
Schortgen et al 2012 27Multicentre, randomised controlled trial of external cooling in patients with fever and septic shock receiving mechanical ventilation in seven centres in France; n=200
  • External cooling significantly reduced body temperature
  • External cooling did not alter the proportion of patients who had a 50% reduction in vasopressor dose after 48 hours
  • Day-14 mortality was significantly lower in the patients assigned to external cooling but there was no significant difference between the groups in terms of ICU or in-hospital mortality

Abbreviations: ARDS: Acute Respiratory Distress Syndrome; ICUs: Intensive Care Units.

Slides and Audio from ‘Fever: Friend or Foe?’ at SMACC 2013

  1. William Osler. The study of the Fevers of the South. JAMA 1896; 21: 999–1004 (1896)
  2. Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, (2003) Current epidemiology of septic shock: the CUB-Rea Network. Am J Resp Crit Care Med 168: 165-172 PMID: 12851245 [Free Full Text]
  3. Niven DJ, Stelfox HT, Laupland KB, (2012) Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. 2013 Jun;28(3):303-10. doi: 10.1016/j.jcrc.2012.09.009. Epub 2012 Nov 14. PMID: 23159136
  4. Jefferies S, Weatherall M, Young P, Eyers S, Perrin KG, Beasley CR, (2011) The effect of antipyretic medications on mortality in critically ill patients with infection: a systematic review and meta-analysis. Crit Care Resusc 13: 125-131. PMID: 21627583 [Free Full Text]
  5. Longworth KE, Smith BL, Staub NC, Steffey EP, Serikov VB, (1996) Use of detergent to prevent initial responses to endotoxin in horses. Am J Vet Res 57: 1063-1066 PMID: 8807023
  6. LeMay DR, LeMay LG, Kluger MJ, D’Alecy LG, (1990) Plasma profiles of IL-6 and TNF with fever-inducing doses of lipopolysaccharide in dogs. Am J Physiol 259: R126-132 PMID: 2197879
  7. Parrott RF, Vellucci SV, Goode JA, (1999) Studies of endotoxin-dependent fever in pre-pubertal pigs following acute activation of the pituitary-adrenocortical axis: towards a new hypothesis of fever regulation. Res Vet Sci 66: 85-91 PMID: 10208885
  8. Leon LR, White AA, Kluger MJ, (1998) Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 275: R269-277 PMID: 9688988 [Free Full Text]
  9. D’Alecy LG, Kluger MJ, (1975) Avian febrile response. J Physiol 253: 223-232 PMID: 1204628 PMCID: PMC1348541
  10. MJ K, (1978) The evolution and adaptive value of fever. Am Scientist 66: 38-43 PMID: 623399
  11. Myhre K, Cabanac M, Myhre G, (1977) Fever and behavioural temperature regulation in the frog Rana esculenta. Acta Physiologica Scandinavica 101: 219-229 PMID: 303438
  12. Covert JB, Reynolds WW, (1977) Survival value of fever in fish. Nature 267: 43-45 PMID: 859637
  13. Bernheim HA, Kluger MJ, (1976) Fever: effect of drug-induced antipyresis on survival. Science 193: 237-239 PMID: 935867
  14. Reynolds WW, (1977) Fever and antipyresis in the bluegill sunfish, Lepomis macrochirus. Comp Biochem Physiol C. 57: 165-167 PMID: 20274
  15. Kluger M (1979) The Evolution of Fever Fever: its biology, evolution, and function. Princeton University Press, New Jersey
  16. Horvath SM, Spurr GB, Hutt BK, Hamilton LH, (1956) Metabolic cost of shivering. Journal of applied physiology 8: 595-602 PMID: 13331842
  17. Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, Kushner R, Schmidt GA, Wood LD, (1995) Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Resp Crit Care Med 151: 10-14 PMID: 7812538
  18. Wagner-Jauregg J (1927) The treatment of dementia paralytica by malaria innoculation Nobel Lectures: Physiology or Medicine 1922-1941. Elsevier, New York, pp. 159-169 [Free Full Text]
  19. Owens C, (1936) The value of fever therapy for gonorrhea. JAMA 107: 1942-1946
  20. Bernard GR, Reines HD, Halushka PV, Higgins SB, Metz CA, Swindell BB, Wright PE, Watts FL, Vrbanac JJ, (1991) Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition. Am Rev Respir Dis 144: 1095-1101 PMID: 1952438
  21. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB, (1997) The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. NEJM 336: 912-918 PMID: 9070471 [Free Full Text]
  22. Memis D, Karamanlioglu B, Turan A, Koyuncu O, Pamukcu Z, (2004) Effects of lornoxicam on the physiology of severe sepsis. Crit Care 8: R474-482 PMID: 15566594 PMCID: PMC1065065
  23. Morris PE, Promes JT, Guntupalli KK, Wright PE, Arons MM, (2010) A multi-center, randomized, double-blind, parallel, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for the treatment of fever in critically ill and non-critically ill adults. Crit Care 14: R125 PMID: 20591173 PMCID: PMC2911773
  24. Haupt MT, Jastremski MS, Clemmer TP, Metz CA, Goris GB, (1991) Effect of ibuprofen in patients with severe sepsis: a randomized, double-blind, multicenter study. The Ibuprofen Study Group. Crit Care Med 19: 1339-1347 PMID: 1935150
  25. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM, (2005) The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surgical infections 6: 369-375 PMID: 16433601
  26. Niven DJ, Stelfox HT, Leger C, Kubes P, Laupland KB, (2012) Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: A pilot randomized clinical trial. J Crit Care. 2013 Jun;28(3):296-302. doi: 10.1016/j.jcrc.2012.08.015. Epub 2012 Oct 24. PMID: 23102531
  27. Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, Dellamonica J, Bouadma L, Cook F, Beji O, Brun-Buisson C, Lemaire F, Brochard L, (2012) Fever control using external cooling in septic shock: a randomized controlled trial. Am J Resp Crit Care MEd 185: 1088-1095 PMID: 22366046

Intensivist in Wellington, New Zealand. Started out in ED, but now feels physically ill whenever he steps foot on the front line. Clinical researcher, kite-surfer  | @DogICUma |

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