Should Fevers Accompanying Infections Always Be Treated With Analgesics?

Every age likes to think itself enlightened, and we doctors are especially prone to believe that all our actions are rational by contrast with those of our brethren who preceded us. In actual fact, of course, much of what we do is tried but not necessarily tested. Doctors are often in the position of having to do something without really knowing whether what they do is good, bad or indifferent.

An example of an untested practice that has long continued is that of giving patients with infections febrifuges, substances that lower the body temperature. This practice was based on a crude, if understandable, logic: since fever is a symptom or sign of illness, it seems to stand to reason that you improve the illness by reducing or abolishing the symptom or sign. After all, if there are no symptoms or signs, there is no illness. Moreover, if the temperature is raised high enough, death always ensues. Hence, levels of fever should be lowered.

This way of thinking has been challenged, however, by evolutionary biologists among others. If the body responds to infection with fever, there must be a reason for it. Indeed, fever has been shown to increase the efficiency of immune cells and inhibit the growth of infective agents. Seriously infected persons who do not have a raised temperature have a worse prognosis than those who do.

A team from Australia and New Zealand tried to answer the question of whether the routine administration of the analgesic febrifuge, acetaminophen, to infected, critically ill persons in intensive care units improved or worsened their prognosis: a question to which the answer was not known. The results of their trial are reported in a recent edition of the New England Journal of Medicine.

The authors assigned 700 patients randomly to receive intravenous acetaminophen or placebo immediately on arrival in ICU. Ten of them subsequently withdrew their consent to participation in the experiment, but that is not enough to have affected the results. The measures of success or failure were the number of days patients remained in ICU and their death rate.

Overall there was no difference. The patients who were given acetaminophen had slightly reduced temperatures during their stay in ICU (about a third of a degree centigrade) but they spent neither a shorter period in ICU nor did fewer of them die. The slight lowering of the temperature by the drug was clinically unimportant and reinforces the message that it is patients whom doctors treat, not physiological measurements. Somewhat surprisingly to me, patients who received acetaminophen suffered no serious side-effects, such as liver damage, from the drug.

In short, acetaminophen did neither good nor harm: except, of course, that it cost something. Whether that is a benefit or a harm depends on whose point of view that you take.

The study had limitations. Acetaminophen was given only for a short time (it was stopped when the patient ceased to be feverish). Perhaps if it had been given for longer the results would have been different. And within the results was a curious anomaly: although the results overall were equal in the two groups, among those patients who survived, those given acetaminophen spent a shorter time in ICU than those given placebo, but among those patients who died, patients given acetaminophen spent longer in ICU than those given placebo. The authors delicately say that this strange result “must be regarded as hypothesis-generating” – that is to say, they cannot explain it.

The slight lowering of temperature brought about by the drug might have influence physicians’ decision to discharge them from the ICU, or it might be that it had a real biological effect: one cannot tell from these results. This means, of course, that further research is required. It always is.