Fever – is it cool to be hot?

What?

A 60-year-old female has presented to the ED with a cough and fever for 2 days. She has her observations recorded in triage and has a fever of 38.1C (tympanic). She otherwise feels well and does not trigger the sepsis screening tool. She has no pain and appears comfortable as she walked into the department. A member of the nursing team asks you to prescribe 1g paracetamol (PO) to reduce her fever…..

So what?

We give paracetamol in the ED to lower temperature, this will be happening hundreds of times every day in the UK. In fact, I think you’re sometimes more likely to get it for fever than you are if you’re in pain. This is bad. It just doesn’t make any sense to have this “knee-jerk” reaction everytime we see someone with a fever. You need to look at your patient and as with everything we do, we need to think about why we are doing it.

Just because paracetamol is cheap and has a good safety profile doesn’t mean we should be thinking about it any less than any other drug we administer. If we were talking about giving TPA to lower fever, then we’d be really be considering the evidence as its expensive and has huge effects we wouldn’t want.

What are we talking about?

Fever is a preserved physiological response to a wide variety of infectious and non-infectious triggers, which induce, by different methods, upregulation of the thermostatic setpoint in the preoptic area of the hypothalamus, finally resulting in fever. We’re talking about these patients presenting to the ED with a fever, in whom we suspect an infective cause.

We’re not talking about patients with hyperthermia due to environmental factors, use of recreational drugs or malignant hyperthermia, as these involve different pathophysiology, requiring rapid cooling (for which paracetamol doesn’t work).

Whats going on?

Thermoregulation is a fundamental homeostatic mechanism that maintains body temperature within a tightly regulated range. The ability to internally regulate body temperature is known as endothermy and is a characteristic of all mammals and birds.

In humans, the central processing center controlling the thermoregulatory set-point is the hypothalamus.

The core body temperature is tightly regulated around a set point by homeostatic mechanisms under normal physiological conditions.

How are we defining fever?

A threshold value of ≥38.3°C has been recommended by several societies for the diagnosis of fever (most notably the World Health Organisation).

There is a female hormonal-induced variation and a diurnal variation. So, Mackowiak and colleagues found that the mean temperature was 36.8°C, with a range of 35.6 to 38.2°C, the temperature being lower in the morning than in the evening.

How are we recording fever?

The core temperature is important, as a core to peripheral temperature gradient is common in critically ill patients, especially in those who are hypovolaemic, have a low cardiac output or are peripherally vasoconstricted.

We want a core temp which would be pulmonary artery catheter ideally, but more commonly in the ED we use either tympanic or oral.

So what are the potential benefits of fever?

  • Effects on infectious agents – Human pathogens grow under optimal temperatures of 35-37C. Above that, in vitro studies have shown reduced growth of pathogens (Prescott 1999).
  • A progressive rise in the activity of antimicrobial agents dependent on temperature – i.e. the hotter the patient, the better they work (Mackowiak et al 1982).
  • Effects of fever on heat shock response (critical for cellular protection and reducing organ damage) – animal studies (sheep and rats) with abdo + lung sepsis induced show longer survival time with higher temperatures.
  • For the common cold, the use of paracetamol was associated with a longer duration of virus shedding and delayed antibody response……. so patients were symptomatic for longer (Stanley et al 1975 + Graham et al 1990).
  • For children undergoing vaccination programmes, giving paracetamol at the time of vaccination induced a delayed and crucially a lower antibody response to several antigens (Prymula et al 2009).

Some history

Julius Wagner-Jauregg (Nobel prize winner 1927) – went on to become a nazi sympathiser…… so his work doesn’t get talked about that much.

Wagner-Jauregg J: The treatment of dementia paralytica by malaria innoculation. In Nobel Lectures: Physiology or Medicine 1922–1941. Elsevier, New York, 1927: 159–169

Essentially – gave malaria to patients paralysed with neuroshyphilis to make them spike a temperature. This temperature caused resolution of symptoms in 33% of cases i.e. no longer paralysed – the patient was then treated with quinine which cured their malaria.

“he tried in 1917 the inoculation of malaria parasites, which proved to be very successful in the case of dementia paralytica (also called general paresis of the insane), caused by neurosyphilis, at that time a terminal disease.It had been observed that some who develop high fevers could be cured of syphilis.”

In real patients…..

Higher survival in patients who developed fever on the day of bacteraemia.

Reduced mortality in spontaneous bacterial peritonitis with fever >38C (Weinstein et al 1979)

In elderly patients with CAP, afebrile patients had a 29% mortality risk, this dropped to 4% in those who developed a febrile response (Ahkee et al 1997).

Additionally

If you give patients paracetamol you take away your ability to see if they develop a fever (+ removes a SIRS criteria – they might not get the sepsis 6 etc..)… and its crucial for determining the management plans of patients in the ED where you have a not forgetting we have a limited time window to do this.

Fever can lower your a NEWS score by 1 which removing it can reduce there response obtained and the frequency of observations. Paracetamol does nothing to treat the underlying cause, and may only delay diagnosis.

What are the problems of having a fever?

Fever is believed to be harmful, especially in patients with life-threatening illnesses, because febrile responses are known to increase the metabolic rate, minute ventilation, and oxygen consumption.

The conservation of a metabolically costly response across a broad range of animal species suggests however that this response probably has an evolutionary advantage.

Now What?

Paracetamol in fever may not be the simple answer that we are all looking for in patients with an infection. Blindly administering it to patients who are systemically well may infer mild harm to patients, of course if the patient is feeling unwell as a result of the fever then it may infer a significant amount of benefit.

The HEAT study published in the NEJM didn’t show any benefit to routine administration to ITU patients with a fever secondary to an infection with the length of ITU stay or inpatient mortality. What we need is a prospective trial of ED patients looking at the administration in our ED cohort with patient centered outcomes. Until then, I think a sensible approach is to treat the patient but not the number… this means a patient who is not uncomfortable or in pain, can be allowed to have a fever as it may well be beneficial for them (with the caveat that we shouldn’t be withholding paracetamol if they need it though).

 

Rob Fenwick

 

References

Ahkee S, Srinath L, Ramirez J: Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis. South Med J 1997, 90:296–298.

Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L: Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990, 162:1277–1282.

Mackowiak PA, Marling-Cason M, Cohen RL: Effects of temperature on antimicrobial susceptibility of bacteria. J Infect Dis 1982, 145:550-553.

Mackowiak PA, Wasserman SS, Levine MM: A critical appraisal of 98.6°F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA 1992, 268:1578-1580.

Prescott LM: Microbiology. Boston, MA: WCB/McGraw-Hill; 1999.

Prymula R, Siegrist C, Chlibek R, Zemlickova H, Vackova M, Smetana J, Lommel P, Kaliskova E, Borys D, Schuerman L: Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet 2009, 374:1339-1350.

Stanley ED, Jackson GG, Panusarn C, Rubenis M, Dirda V: Increased virus shedding with aspirin treatment of rhinovirus infection. JAMA 1975, 231:1248–1251.

Weinstein MP, Iannini PB, Stratton CW, Eickhoff TC: Spontaneous bacterial peritonitis. A review of 28 cases with emphasis on improved survival and factors influencing prognosis. Am J Med 1978, 64:592–598.

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