Intended for healthcare professionals



BMJ 2004; 328 doi: (Published 26 February 2004) Cite this as: BMJ 2004;328:532

On the dangers of administering antipyretics even to normothermic patients.

The presence of a fever has been associated with the onset of
illnesses and the return to a normal temperature associated with recovery
for so long that a deeply imbedded medical meme is to reduce body
temperature whenever it is abnormally elevated. Has anyone considered the
possibliity that lowering body temprature to abnormally low levels with
antipyretics adminstered to normothermic patients in pain might do harm?

"The credit (or blame) for introducing the term pH, the negative log
of hydrogen ion (H+) concentration, goes to S. P. L. Sørensen (1868-1939),
who apparently tired of writing seven zeros in a paper on enzyme activity
and wanted a simpler designation. Although the use of pH instead of
nanomoles of H+ has been repeatedly challenged, pH has survived in large
part because the behavior of a substance in a chemical system is
proportional to its energy (chemical potential), and this, in turn, is a
logarithmic function of the activity of the substance. A pH electrode
responds to the chemical potential of H+, and thus the instrument provides
a precise and readily obtained measurement of the chemical behavior of H+
in the system, exactly what the chemist, physiologist, and clinician need
to know. The pH of blood, and of neutral water, changes linearly with
temperature, whereas H+ concentration is a log function of

The statement that, "behavior of a substance in a chemical system is
proportional to its energy (chemical potential)", suggests that the
relationship between tissue pH and tissue energetics is primarily a
physical one and only secondarily a biological one (2,3). Futhermore the
statement that, "the pH of blood, and of neutral water, changes linearly
with temperature, whereas H+ concentration is a log function of
temperature", suggests that the Q10 effect is also a physical one rather
than a biological one, the Q10 effect being the 10% increase in basal
metabolic rate that occurs with each degree rise in body temperature.

In biological tissues the chemical potential in the proton gradient
between cytosol and mitochondrial matrix is known as the protonmotive
force which was postulated by the Nobel laureate Peter Mitchell to drive
ATP resyntheis by oxidative phosphorylation (4). In one sense, therefore,
an increase in ATP resynthesis by mitochondria may be driven by a physical
process very similar to that in plants during photosynthesis. In which
case the energy in heat may have been changed into potential energy
stored within a chemical potential by a purely physical process, one
analogous to the increase in Brownian movement and to the increase in
mental and physical activity that occurs in poilkilotherms when the
ambient temperature rises.

If an increase in temperature increases the rate of ATP resynthesis
by mitochondria by a purely physical effect then it must do the same to
ATP resynthesis by glycolysis alone during anaerobic metabolism. In which
case the hypothalmically controlled regulation of body temperature,
arguably largely induced by humorally induced changes in mitochondrial
membrane permeability rather than shivering and sweating, is a very
important determinant of ATP resynthesis. In hyperthyroidism, for example,
the increase in body temperature induced by uncoupling might be
exclusively responsible for the increase in metabolic rate.

What then of antipyretics given to normothermic patients? Might they
derease metabolic rate 10% for every degree the body temperature falls [a
reverse Q10 effect] and decrease the availability of ATP proportionately
[a physical effect of the temperature change]? If the availability of ATP
falls with the administration of antipyretics to normothermic patients
then cellular dysfunction, apoptosis or even necrosis might be induced as
occurs in hypothyroidism.

The claim that ATP resynthesis is solely demand driven needs to be
revised. More importantly the widespread administration of antipyretics
to pyrexial and even normothermic patients needs to be re-evaluated with
some urgency. A fever may be doing good by increasing the availability of
ATP. Very small changes in temperature and for that matter blood and
tissue pH, too small to be detected by current clinical methodology, may
have profound effects upon cellular functioning in all organs including
the brain.

Analysis and Critical Care Medicine. Am. J. Respir. Crit. Care Med.,
Volume 157, Number 4, April 1998, S114-S122

2. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and
acid-base balance.
Br J Anaesth. 1995 May;74(5):591-606.

3. Fiddian-Green RG. Monitoring of tissue pH: the critical
Chest. 1999 Dec;116(6):1839-41

4. Reid RA, Moyle J, Mitchell P. Synthesis of adenosine triphosphate
by a protonmotive force in rat liver mitochondria.
Nature. 1966 Oct 15;212(59):257-8

Competing interests:
None declared

Competing interests: No competing interests

03 March 2004
Richard G Fiddian-Green