Fever has long been recognized as a symptom of disease. Until the past century it was considered a healthy sign; since then this view has changed and the use of drugs to reduce fever has grown quite common. Acting on the revival of interest as to whether the effects of fever are beneficial or harmful, Matthew Kluger and other physiologists began a series of experiments designed to resolve this question. This book synthesizes their research, making a case not only for the beneficial function of fever but also for the re-evaluation of current clinical practices regarding fever.
Originally published in 1979.
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Its Biology, Evolution, and Function
By Matthew J. Kluger
PRINCETON UNIVERSITY PRESSCopyright © 1979 Princeton University Press
All rights reserved.
Regulation of Body
Temperature in the Vertebrates
Why Regulate Body Temperature?
The energy expended by "warm-blooded" organisms, such as ourselves, to regulate our body temperature is enormous: temperature regulation is costly. For example, at low environmental temperatures, people might have to expend 1800 kcal/day, or more, solely to generate the heat necessary to maintain a body temperature of 37°C and perhaps 10% more at febrile temperatures. This expenditure of energy often amounts to over 90% of the total energy used in any given day for performing external work. The energy, of course, comes from the food we eat, and as a result, we must eat an equivalent amount of kcal of food each day just to regulate body temperature. On days when our food intake falls below our daily energy expenditure, we rely on our stores of fat for this source of energy, resulting in a loss of weight. One can calculate, approximately, the amount of energy saved by a resting human-sized organism which does not regulate its body temperature, and therefore remains at a constant environmental temperature, say 20°C. This organism would have a metabolic rate (energy expenditure) roughly equivalent to that of the American alligator, or about 60 kcal/day (Altman and Dittmer 1974). In other words, regulating can cost about thirty times more than not regulating body temperature (1800 kcal/day vs. 60 kcal/day).
Expending and therefore procuring such large amounts of energy have led to numerous adaptations in birds, mammals, and other "warm-blooded" organisms. These adaptations have increased the efficiency of these organisms to obtain, digest, and utilize large volumes of food. Based on the enormous energy cost of regulating body temperature, it is often speculated that there must be some adaptive value in maintaining body temperature at a high and fairly constant level rather than allowing body temperature to fluctuate with the environmental temperature. The adaptive value of regulating body temperature is thought to be related to the effect of temperature on biochemical reactions.
The physiology of any organism can ultimately be reduced to a series of chemical reactions. Most of these reactions are strongly influenced by temperature. The effect of increasing temperature on the rate of increase in biochemical reactions is often greater than can be explained simply by the thermally induced increase in the average kinetic energy of the reacting molecules. For example, many biochemical reactions increase their reaction rate two to threefold over a 10°C rise in temperature (this is often referred to as a "Q10" of 2 or 3). Based on simple molecular kinetics, a 10°C rise in temperature should have increased the reaction rate only a few percent (Giese 1968). In the late 1800s, the Swedish physical chemist Arrhenius proposed that the often logarithmic increase in the reaction rates of biochemical reactions is related to their activation energy. Arrhenius mathematically characterized the effects of temperature on biochemical reactions, pointing out that most biochemical reactions tend to increase logarithmically with increasing temperature to a point of maximization. Above this optimal temperature, the reactions decrease (Johnson et al. 1954). Examples of this profound effect temperature has on biological systems can be seen in its effect on the growth rates of various organisms (Figures 1-3).
Organisms which regulate their body temperature maintain a degree of biochemical stability not found in the non-thermoregulators. Not only have their biochemical reactions evolved to function optimally at or near the regulated body temperature, but, perhaps more importantly, these reactions can now occur in comparative independence of the environmental temperature. A normal reduction in the environmental temperature does not slow the metabolic processes of a thermoregulator like a bird or mammal.
Birds, mammals, and representatives from some other groups of organisms are thermoregulators called "endotherms." Endotherms have the capability of internally generating sufficient amounts of heat to raise their body temperature considerably above the environmental temperature. Endotherms have been freed, to some extent, from the effects of environmental temperature. They can remain active, maintaining optimal conditions for their biochemical reactions, over a wide range of environmental temperatures. Subtle changes in environmental temperature which would markedly affect the biochemical reactions of nonthermoregulators do not affect endotherms.
There is another group of thermoregulators which, unlike the endotherms, lack the metabolic machinery to generate internally large quantities of heat — the ectotherms. Reptiles, fishes, and representatives from many other groups of animals are ectotherms. An ectotherm relies primarily on behavioral adjustments to maintain a fairly constant body temperature. A lizard such as the desert iguana, for example, regulates its body temperature at 39°C ± 1°C by moving into the sunlight when its body temperature falls below 38°C and into the shade when its body temperature rises above 40°C. This form of thermoregulation, which is energetically cheaper than generating the heat internally, nonetheless provides the advantages of biochemical stability found in the endotherms. However, the ectotherm can only regulate its body temperature in environments which have the appropriate thermal profile. At night, on overcast days, or during the winter, the ectotherm "slows down" as its body temperature falls toward the environmental temperature.
The regulation of body temperature, therefore, allows an organism to maintain a thermodynamically stable internal environment in which increases or decreases in the rates of millions of individual biochemical reactions can be changed by the organism (by changing the concentrations of enzymes or substrates) without the need to compensate for changes in environmental temperature.
Why is Body Temperature of Thermoregulators Generally between 35° and 42°C?
It is a curious fact that most terrestrial temperature regulators do their regulating somewhere between 35° and 42°C. Theoretically, a terrestrial thermoregulator could have evolved a system to maintain a reasonably constant body temperature at 5°C or perhaps even 95°C, temperatures substantially above and below the freezing and boiling points of body fluids, respectively. But why within 35° to 42°C?
The upper thermal limit for the survival of most organisms is about 45°C. Above this temperature, proteins tend to denature (lose their tertiary structure). Thus, the thermoregulators are often within a few degrees of their upper lethal limit. The explanation for the regulation of body temperature generally within 10°C of this upper lethal limit is thought to be related to the effects of temperature on biochemical reactions, to the physics of heat exchange between an organism and the environment, and to the average temperature of the earth.
To regulate body temperature at any given level, an organism's rate of heat gain (sum of rate of heat absorbed from the environment + rate of internal heat production) must equal its rate of heat loss. When these are out of balance, body temperature will rise or fall
Heat Gain = Heat Loss (1)
depending on which side of equation (1) is greater. Heat is exchanged between an organism and its environment by four physical processes: conduction, convection, radiation, and evaporation. These forms of energy exchange will be described briefly.
Why between 35° and 42°C?
1. Conduction. When I touch the metal bookcase in my office, it feels colder than the surrounding air temperature.
This is because air is a poor conductor of heat (a good insulator) and metal is a good conductor of heat (a poor insulator).
Heat flows from my hand, which might be at 32°C, to the metal bookcase, which might be at 22°C, by a process known as conduction. Heat, which flows from a higher to a lower temperature, is passed directly to the bookcase. The temperature of my hand will fall as the result of this transfer of heat; the temperature of the bookcase will rise. The process of heat transfer by conduction occurs by the movement of heat energy between adjacent molecules and occurs without any mass motion in the medium through which this energy is moving. Conduction of heat can be represented by the following equation:
K/t = A k/L (T1 – T2) (2)
where, K = conductive heat exchange
t = time
A = area
L = distance between T1 and T2
k = coefficient of conductivity
T1 and T2 = temperatures of two objects
This equation asserts that the rate of conductive heat transfer between two objects is related to the surface area in contact, the distance the heat must travel, the thermal conductivities of the substances, and the difference in temperature between the two objects. If the metal bookcase were at a temperature above my hand's temperature, then clearly heat would be gained from the bookcase and my hand's temperature would rise.
2. Convection. Heat is also lost from our bodies by the transfer of heat from our skin surface to the fluid medium which surrounds us, this medium being either air or water. The rate of heat lost by convection can be represented by the following equation:
C/t = c A (T1 – T2) (3)
where, C = convective heat exchange
t = time
c = convective heat transfer coefficient
A = area
T1 and T2 = temperatures of two objects
As in conductive heat loss, convective heat exchange is proportional to the area in contact with, in this case, the medium, and to the difference in temperature between the two objects. It is also dependent upon the coefficient of convection. The coefficient of convection is related to the type of medium in which the exchange of heat is occurring, and the velocity of movement of the medium, as well as other characteristics. The increase in convective heat loss on windy days (c increases) is a well-known phenomenon and goes into forming the commonly used wind-chill index to describe the subjective sensation of coldness.
3. Radiation. All objects above absolute zero (– 273°C) emit energy in the form of radiation. We are constantly gaining and losing heat by radiation based on the following equation:
R/t = σe1e2A(T14 – T24) (4)
where, R = radiant heat exchange
t = time
σ = Stefan-Boltzmann constant
e1, e2 = emissivities of the radiating objects
A = area
T1, T2 = temperatures of radiating objects (in absolute temperature)
Without even attempting to describe in any detail the significance of σ, or the emissivities of the radiating objects, one can see that the rate of heat exchange by radiation is, as in conduction and convection, related to the area and to the difference in temperature between the two objects (in this case to the fourth power of the absolute temperature).
For our purposes, the key point about conduction, convection, and radiation is that they are all dependent upon a difference in temperature. Heat flows from a higher temperature to a lower temperature.
4. Evaporation. Heat is lost from our bodies by evaporation of water from our respiratory tract or from our skin (sweating). During periods of heat stress induced by exercise (an internal heat stress) or by exposure to high environmental temperatures, we can lose a liter or more of sweat each hour. Each liter of sweat which evaporates from our skin surface removes approximately 580 kcal (latent heat of vaporization of water at skin temperature). Sweating is, therefore, an enormously effective mechanism for losing heat. The rate of heat lost by evaporation is given by equation (5):
E/t = A b (V.P.1 – V.P.2) (5)
where, E = heat lost by evaporation
t = time
A = area
B = coefficient of evaporation
V.P.1, V.P.2 = vapor pressures of surface where water is evaporating and the vapor pressure of the air surrounding that surface
The amount of heat lost by evaporation is related to the area exposed to evaporation, a coefficient of evaporation (which is a function of wind velocity, latent heat of vaporization, and other variables), and the vapor pressure differences between the evaporating surface and the air. When the vapor pressure (or partial pressure) of water on our skin surface is equal to the vapor pressure of the air, then no evaporation occurs. The sweat simply drips off our bodies and does not contribute to cooling us. This is what happens when the relative humidity is 100%. (The relative humidity is defined as the ratio of the environmental vapor pressure to the maximum or saturated vapor pressure at the same temperature.) Under these conditions, the vapor pressure on our skin surface (which is generally close to, or at, the saturated level) equals the saturated vapor pressure of the surrounding air.
Figure 4 summarizes the basics of heat exchange between an organism and its environment. For more detailed accounts of heat exchange, the reader is referred to Carlson and Hsieh (1970), Brengelmann (1973), Gates (1972), Lowry (1967), and Birkebak (1966).
What does this brief introduction to energy exchange between an organism and its environment have to do with the regulation of body temperature between 35° and 42°C? The mean or average temperature of the earth on its surface is about 16°C (Gates 1972). Obviously, temperatures in different areas of the world and at different times of the day and year vary significantly from 16°C; but generally, a thermoregulator will be above the environmental temperature. Let us assume for a moment that an animal regulates its body temperature at 25°C. When the environmental temperature is at the mean earth temperature of 16°C, the heat which the animal produces by its metabolic processes would be dissipated to the environment by the processes of conduction, convection, radiation, and evaporation. When the environmental temperature is 30°C, a temperature which often occurs during the summer months even in temperate climates, the processes of conduction, convection, and radiation would serve to increase the animal's body temperature. This is because heat would now flow from the higher environmental temperature to the lower temperature of the thermoregulator — see equations (2-4). The animal must now rely entirely on evaporation of water to maintain its temperature at 25°C. Because evaporation of water removes such large quantities of heat, the animal would still face little difficulty regulating its body temperature at 25°C. There are, however, two potential problems involved in relying completely on evaporation as a means of maintaining a constant body temperature. The first occurs for the thermoregulator when water is scarce. In certain areas of the world, perhaps a desert during a summer day, the air temperature might approach 50°C. The hot desert winds tend to warm the individual by convective heat transfer from the environment to the individual. However, since the air is dry, a person regulates his body temperature by the evaporation of water. To maintain a body temperature of 37°C, the individual might have to lose up to nineteen liters of water over a twelve-hour period (Gates 1972). To regulate body temperature at 25°C, under these conditions, would be an impossibility. Clearly, the desert during the heat of a summer day is not an environment which thermoregulators prefer, even those that regulate between 35° and 42°C. This is why so many desert animals are nocturnal. The reliance on the evaporation of water to maintain a constant body temperature will not work effectively for desert dwellers, or for any organisms which may face periodic shortages of water.
Excerpted from Fever by Matthew J. Kluger. Copyright © 1979 Princeton University Press. Excerpted by permission of PRINCETON UNIVERSITY PRESS.
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Table of Contents
- Frontmatter, pg. i
- Contents, pg. vii
- List of Tables, pg. xi
- List of Figures, pg. xiii
- Acknowledgments, pg. xvii
- Introduction, pg. xix
- 1. Regulation of Body Temperature in the Vertebrates, pg. 1
- 2. The Biology of Fever, pg. 51
- 3. The Evolution of Fever, pg. 106
- 4. The Adaptive Value of Fever, pg. 129
- References, pg. 167
- Index, pg. 191