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Three Part Question

In [adults with fever secondary to infection] does [treating the pyrexia][reduce morbidity and mortality]?

Clinical Scenario

A 50 year old patient attends the Emergency Department with a fever, and symptoms suggestive of a urinary tract infection. He has a T 39.1, HR 110, RR 20.
As you are making your assessment, the staff nurse appears at your elbow, anxious to administer 1g paracetamol for his pyrexia.
You muse that as pyrexia in response to infection is a result of thousands of years of evolution, it may well serve a purpose. You wonder whether treating pyrexia has a positive or detrimental effect on the body’s response to infection.

Search Strategy

In [adults with fever secondary to infection] does [treating the pyrexia][reduce morbidity and mortality]?

MEDLINE; ((fever OR febrile OR pyrexia*) AND (acetaminophen OR paracetamol OR aspirin OR antipyretic OR cooling)).ti,ab [Limit to: Humans and (Age Groups All Adult 19 plus years) and English Language]
Plus manual searching and reference review

Search Outcome

363 results
Of which 4 papers directly address the question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Valerio Gozzoli, MD; Patrick Schottker, MD; Peter M. Suter, MD; Bara Ricou, MD 2001 Switzerland	38 surgical intensive care unit patients without neurotrauma or severe hypoxemia and with fever (temperature >38.5°C) and systemic inflammatory response syndrome.	Open randomized prospective trial. Randomized to external cooling vs no treatment of fever.	Defervescence at 24 hr	No difference	Small study, powered only for primary outcome (defervescence at 24 hr). External cooling differs from standard treatment of pyrexia. Excluded patients with significant hypoxaemia.
			Discomfort	No difference
			Proven infection	No difference
			ICU length of stay	No difference
			Mortality	No difference
Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Alhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasc 2005 USA	82 patients admitted to trauma intensive care unit. Excluded brain injury patients.	Open prospective randomized controlled trial. Patients randomized to 'aggressive' treatment group received paracetamol and external cooling for temperatures >38.5 C, patients randomized to the 'permissive' group had treatment of temperature greater than 40 C with paracetamol (until temperature below 40 C)	Proven infection (positive blood culture)	Higher in aggressive group, 131 vs 85. p=0.26	Small study, stopped at interim analysis due to mortality difference.
			Mortality	Higher in aggressive group. 7 vs 1. p=0.06
Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, Kushner R, Schmidt GA, Wood LD 1995 USA	12 febrile, critically ill, mechanically ventilated ICU patients. Mean APACHE score 22.4	Physiological study. Patients cooled, with monitoring of oxygen consumption and energy expenditure.	Oxygen consumption	Reduced with cooling from 39.4C to 37C, from 359ml/min, to 295 ml/min p<0.01	Small, non- blinded study. No comparison group. No placebo. Different patient group to that encountered in the ED. Clinical significance of findings not clear.
			Energy expenditure	Decreased with cooling, from 2481 kcal/day, to 1990 kcal/day p<0.01
Graham N, Burrell C, Douglas R, Debelle P 1990 Australia	60 healthy volunteers	Double blinded placebo controlled volunteer study. Volunteers deliberately infected with rhinovirus. Randomised to receive aspirin, paracetamol, ibuprofen or placebo. Symptoms, mucus production, duration of symptoms and antibody response measured.	Antibody response	Reduced in aspirin and paracetamol groups	Significant pyrexia uncommon therefore results may represent anti-inflammatory response rather than effect of treatment of pyrexia. Small numbers.
			Nasal symptoms	Increased in aspirin and paracetamol groups

Comment(s)

Pyrexia in response to infection is an ancient response in evolutionary terms, and is present in fish, reptiles, birds and mammals. Fever has been suggested to increase leucocyte mobility, phagocytosis, T cell proliferation and action of interferon. However it may increase metabolic rate and oxygen demand, with consequent effects on the cardiorespiratory system. Animal studies have suggested that elevated body temperature reduces mortality from infection in cold blooded mammals.

Clinical Bottom Line

Some limited evidence that antipyretic therapy may have an adverse effect on the immune response to infection, which may translate into poorer outcomes. A permissive approach to fever does not appear to be detrimental. In a subgroup of patients with significant hypoxaemia or limited capacity for oxygen delivery, temperature reduction may be beneficial.

References

1. Valerio Gozzoli, MD; Patrick Schottker, MD; Peter M. Suter, MD; Bara Ricou, MD Is It Worth Treating Fever in Intensive Care patients? Preliminary Results From a Randomized Trial of the Effect of External Cooling Archives of Internal Medicine Jan 2001, Vol 161:121-123
2. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Alhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surgical Infections 2005; 6 (4): 369-75
3. Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, Kushner R, Schmidt GA, Wood LD Effect of cooling on oxygen consumption in febrile critically ill patients. American Journal of Respiratory and Critical Care Medicine 1995; 151 (1): 10-14
4. Graham N, Burrell C, Douglas R, Debelle P Adverse effects of aspirin, acetaminophen and ibuprofen on immune function, viral shedding and clinical status in rhinovirus infected volunteers. Journal of Infectious Diseases 1990;162: 1277-1282