Medical Physiology, 3rd Edition

Hypothermia, Hyperthermia, and Fever

Hypothermia or hyperthermia occurs when heat transfer to or from the environment overwhelms the body's thermoregulatory capacity

Although the body's temperature-regulating machinery is impressive, its capabilities are not limitless. Any factor that causes sufficiently large shifts—either negative or positive—in the rate of heat storage (see Equation 59-1) could result in progressive hypothermia or hyperthermia (see Equation 59-6). Because humans must operate within a fairly narrow core-temperature range, such temperature changes could become life-threatening.

The most common environmental condition causing excessive hypothermia is prolonged immersion in cold water. Water has a specific heat per unit volume that is ~4000 times that of air and a thermal conductivity that is ~25 times that of air. Both properties contribute to a convective heat-transfer coefficient (h_convective in Equation 59-4) that is ~100-fold greater in water than it is in air. The h_convective is ~200 kcal/(hr ⋅°C ⋅ m²) at rest in still water but ~500 kcal/(hr ⋅ °C ⋅ m²)while swimming. The body's physiological defenses against hypothermia include peripheral vasoconstriction (which increased insulation) and shivering (which increases heat production), but even these measures do not prevent hypothermia during prolonged exposure because of water's high thermal conductivity. A thick layer of insulating fat retards heat loss to the water and postpones or even prevents hypothermia during prolonged exposures. Endurance swimmers have used this knowledge to protect themselves by applying a thick layer of grease to the skin surface before an event (now, more commonly, they don a wetsuit). Herman Melville noted this principle in 1851, when he referred to the low thermal conductivity of fat:

For the whale is indeed wrapt up in his blubber as in a real blanket. … It is by reason of this cozy blanketing that the whale is enabled to keep himself comfortable in all seas. … this great monster, to whom corporeal warmth is as indispensable as it is to man.

—Moby Dick

Like blubber, clothing adds insulation between skin and environment and thus reduces heat loss during exposure to the cold. The more skin one covers, the more one reduces the surface area for direct heat loss from skin to environment by convection and radiation. Adding layers of clothing increases the resistance of heat flow by trapping air, which is an excellent insulator. During heat exposure, the major avenue for heat loss is evaporation of sweat. Because evaporation also depends on the surface area available, the amount of clothing should be minimized. Wetting the clothing increases the rate of heat loss from the skin because water is a better conductor than air. Water also can evaporate from the clothing surface, which removes heat from the outer layers and increases the temperature gradient (and rate of heat loss) from skin to clothing.

The most common environmental condition that results in excessive hyperthermia is prolonged simultaneous exposure to heat and high ambient humidity, particularly when accompanied by physical activity (i.e., elevated heat-production rate). The ability to dissipate heat by radiation falls as the radiant temperature of nearby objects increases (see Equation 59-3), and the ability to dissipate heat by convection falls as ambient temperature increases (see Equation 59-4). When ambient temperature reaches the mid-30s (°C), evaporation becomes the only effective avenue for heat dissipation. However, high ambient humidity reduces the skin-to-environment gradient for water vapor pressure, which reduces evaporation (see Equation 59-5). The combined reduction of heat loss by these three pathways can markedly increase the rate of heat storage (see Equation 59-6), causing progressive hyperthermia.

It is uncommon for radiative or convective heat gain to cause hyperthermia under conditions of low ambient humidity, because the body has a high capacity for dissipating the absorbed heat by evaporation. Radiative heat gain can be excessively high during full exposure to the desert sun or during exposure to heat sources such as large furnaces. The most obvious protections against radiative hyperthermia are avoiding radiant sources (e.g., sitting in the shade) and covering the skin with loose clothing. The latter screens the radiation while allowing air circulation underneath the clothing and thereby maintaining evaporative and convective losses.

Exercise raises heat production, which is followed by a matching rise in heat loss, but at the cost of a steady-state hyperthermia of exercise

At the onset of muscular exercise, the rate of heat production increases in proportion to exercise intensity and exceeds the current rate of heat dissipation; thus, heat storage occurs and core temperature rises (Fig. 59-5). This rise in the temperature of the local environment of the preoptic warmth-sensitive neurons increases their discharge rate, which increases the neural output that activates heat dissipation (see Fig. 59-4). As a result, skin blood flow and sweating increase as T_core rises, promoting an increase in the rate of heat transfer from core to environment and slowing the rate at which T_core rises. However, heat dissipation during exercise does not increase enough both to eliminate the already-acquired heat storage and to balance the ongoing heat production. Thus, the mildly elevated steady-state T_core persists as long as exercise continues.

FIGURE 59-5 Whole-body heat balance during exercise.

The elevated T_core during exercise may be one aspect of the body's “central command” for exercise and is necessary to maintain the elevated discharge of the preoptic warmth-sensitive neurons in order to sustain increased activity of the thermal effectors for heat dissipation. In the example illustrated in Figure 59-5, metabolic heat production rises rapidly to its maximal level for the particular level of exercise underway. However, evaporative heat loss increases only after a delay and then rises slowly to its maximal level, driven by increasing body temperature. In this example, the result is net storage during the first 15 minutes. The slight initial drop in T_core at the onset of exercise is caused by flushing out of blood from the cooler peripheral circulation when the muscle and skin beds vasodilate in response to the onset of exercise. Note also that mean skin temperature decreases during exercise because of the increased evaporative cooling of the skin caused by sweating. N59-5

Contributed by Ethan Nadel

Physical training reduces the hyperthermia of exercise by reducing the threshold for sweating (so that sweating begins earlier) and increasing sweating sensitivity (so that a given hypothalamic drive produces more sweating); it thus provides a greater margin of safety between operating and limiting temperatures for exercise (eFig. 59-2). To the extent that training enhances sweat gland function (evaporative heat loss), reliance on cutaneous circulation (convective heat loss) falls, while preserving blood flow to muscle. The relative dehydration caused by continuous water losses during prolonged exercise elevates the temperature threshold for sweating and reduces the sensitivity (see eFig. 59-2). The result is a higher core temperature during exercise.

EFIGURE 59-2 Thermoeffector responses with physical training.

Fever is a regulated hyperthermia

Whereas hyperthermias such as that resulting from exercise in a hot environment arise from incomplete compensation by the thermoregulatory system for an imposed heat load, fever is a regulated elevation of core temperature induced by the central thermoregulatory system itself.

In response to a variety of infectious and inflammatory stimuli, macrophages and, to a lesser extent, lymphocytes release cytokines into the circulation (Fig. 59-6). Cytokines (see p. 68) are a diverse group of peptides and proteins involved in numerous tasks, among which are serving as the messenger molecules of the immune system. The first step in the host defense response is the immune response to foreign substances, including stimulation of T-lymphocyte proliferation, of natural killer cells, and of antibody production. The second is the acute-phase response, a diffuse collection of host reactions, including fever production, lethargy, and hyperalgesia, which apparently support the immunological response to, and the body's recovery from, infection or trauma. Finally, cytokines such as interleukin-1β (IL-1β) act as endogenous pyrogens (Table 59-3) in a signaling cascade that induces peripheral (e.g., in liver) and CNS production of prostaglandin E₂ (PGE₂; see Fig. 3-11). IL-1β, for example, could interact with the endothelial cells in a leaky portion of the blood-brain barrier (see pp. 284–287) located in the capillary bed of the organum vasculosum laminae terminalis (OVLT; see pp. 284–285). The OVLT is highly vascular tissue that lies in the wall of the third ventricle (above the optic chiasm) in the brain. IL-1β triggers endothelial cells within the OVLT to release PGE₂, which then diffuses into the adjacent preoptic hypothalamus to drive the febrile response.

FIGURE 59-6 Host defense response.

PGE₂ inhibits warmth-sensitive neurons in the preoptic area—akin to the action of stimulated skin cold thermoreceptors—and activates the thermal effectors (see pp. 1200–1201) for heat retention (cutaneous vasoconstriction) and heat production (brown adipose tissue thermogenesis, and shivering or “chills”), which results in an increase in T_core. This sequence is in sharp contrast to the hyperthermia of exercise, in which the rise in T_core due to muscle heat production provides a strong and unimpeded stimulus for the preoptic warmth-sensitive neurons to increase the activity of the thermal effectors for heat defense. In contrast, in fever, the excitatory effect of the elevated T_core cannot compete with the strong inhibition of the preoptic warmth-sensitive neurons elicited by the local increase in PGE₂, and activation (via disinhibition) of the thermal effectors for cold defense prevails. N59-6

Contributed by Ethan Nadel

EFIGURE 59-3 Exercise hyperthermia versus fever. A, The top panel shows how, during exercise, heat production temporarily exceeds heat loss, which results in net heat storage. The middle panel shows that the rate of heat storage is highest initially and falls to zero in the new steady state. Finally, the bottom panel shows that as body core temperature rises away from the set-point (T_set), the error signal gradually increases. In the new steady state, the error signal is maximal and sustained. B, The top pair of panels show how, during fever, net heat storage can occur because of either reduced heat loss or increased heat production. The third panel shows that, as in exercise, the rate of heat storage is highest initially. The bottom panel shows that as body core temperature rises, it approaches the new elevated set point. Thus, the error signal is initially maximal and gradually decreases to zero in the new steady state.

Once the PGE₂ production falls—perhaps due to administration of an anti-inflammatory drug that inhibits PGE₂ synthesis (see Box 3-3)—the elevated T_core can now produce a marked stimulation of the preoptic warmth-sensitive neurons, resulting in an inhibition of the thermal effectors for heat production and a strong stimulation of those for heat loss, and the fever “breaks.”

In both exercise and fever, behavioral thermoregulatory responses support those autonomic and shivering responses being directed by the neurons in the preoptic area. During exercise, one feels warm, and this deviation from thermal comfort drives behaviors such as removing clothing or splashing cold water on the body to cool it. In contrast, during the onset of a fever, one feels cold and may choose to put on additional clothing or blankets to warm the body. If fever strikes when the patient is in a hot environment in which the cutaneous vessels are dilated, cutaneous vasoconstriction will occur to reduce heat loss. In contrast, if the patient is in a cool environment in which the cutaneous vessels are already constricted, increased thermogenesis will occur in brown adipose tissue and through shivering (chills). However, because the thermal effectors activated in cold defense are the same as those activated during fever, it may be difficult to produce a significant febrile elevation of T_core in a fairly cold environment.

The value of fever in fighting infection is still debated. A popular hypothesis is that the elevated temperature enhances the host's response to infection. This view is supported by the observation that, in vitro, the rate of T-lymphocyte proliferation in response to interleukins is many-fold higher at 39°C than it is at 37°C.