Monitoring the Core Temperature

A history of clinical thermometry is available¹¹¹ as are good overviews of the assessment of core temperature.^10,32,201 Sites for taking the temperature, in order of increasing invasiveness, include the forehead, axilla, oral cavity, tympanum, rectum, esophagus, bladder, and pulmonary artery. There is no clear-cut choice regarding the best site to monitor; particular situations demand different techniques. Thermometers that have been employed clinically include mercury-in-glass thermometers (which are now obsolete), electronic thermometers, tympanic radiation thermometers, and liquid crystal thermometers. Whatever instrument is used should have an accuracy of ±0.1° C (0.2° F). The handheld electronic thermometer is a good choice for field emergencies.

Measuring Instruments

The handheld electronic thermometer has replaced the mercury-in-glass thermometer, and it has been widely used for many years. Electronic thermometers can make use of either thermistors or thermocouples as sensors; they have the requisite degree of accuracy, and they are very flexible in application. Although an equilibration time of 1 minute is specified for the typical probe, this is largely because of the need for a stiff casing for ease of insertion; smaller probes are available that can equilibrate in seconds. The digital display of these instruments reduces errors, and the probes can be left in place for continuous monitoring. A quality instrument with a wide range of interchangeable probes is important. Even then, these devices are subject to the usual problems inherent with electronic instruments and rarely have a range low enough to monitor skin temperature in cold environments. A second electronic thermometer with a wide temperature range is important for measuring skin temperature and as a backup for the standard clinical thermometer. Alternate probes and spare batteries for both instruments are essential.

Tympanic infrared radiometers are often used in hospital settings. However, even in this relatively predictable environment, some controversy exists regarding their ability to accurately assess core temperature. These instruments monitor the electromagnetic radiation that emanates from the ear canal; various manufacturers make use of different and complicated electronic circuitry to produce a temperature display. An advantage is that the reading takes only a few seconds,³² but questions remain regarding the overall accuracy of the measurement displayed. In a laboratory situation in which the auditory canal is plugged with a sponge and the probe measures only radiation that emanates from the tympanum, infrared tympanic thermometry provides an excellent estimate of the core temperature.¹⁷⁴ In clinical settings, the results are less consistent. In one study, infrared tympanic thermometry produced core temperatures that were much more variable than rectal temperatures. Even after correcting for the higher rectal values (0.5° C [0.9° F]), tympanic measurements still inaccurately displayed one-third of the temperatures that were more than 37.7° C (99° F). An extended training program did not significantly alter the accuracy of the readings.¹⁴⁷

In one instance, a child who arrived at an emergency department presented with tachycardia and skin vasoconstriction. Separate tympanic infrared thermometers gave core temperatures of 36.4° and 37.6° C (97.5° and 99.7° F); the rectal temperature was determined to be 42.2° C (108° F).¹⁵⁸ Alternatively, in a hospital setting with a trained operator and immobile patients, two brands of infrared tympanic thermometers produced readings that were closer to pulmonary artery readings than those obtained from the axilla or the rectum.¹⁵⁵

The potential benefits of a continuous and easily applied core temperature monitor have led to repeated attempts to validate liquid-crystal thermometers, which are typically placed on the head or neck surface. Unfortunately, the temperature readings produced by this method are not reliable.^10,111 Because these measurements are compromised by the thermoregulatory vascular changes associated with heat conservation and heat dissipation and by changes in ambient temperature,⁸⁰ they are particularly unsuited for field emergency measurements.

Measurement Sites

Although the deep internal temperatures of normothermic humans are reasonably similar, no specific anatomic site represents the “official” core temperature. The temperature at each location is a consequence of a combination of the local metabolic rate, local perfusion rate, proximity to the outer shell, and proximity to other locations that have differing rates of metabolism and perfusion. Nevertheless, because of the generally high overall rates of tissue perfusion in mammals, deep core temperatures rarely differ by more than 0.5° C (0.9° F). The temperature of the pulmonary artery is a good reference temperature for the overall status of the thermal core. At steady state, accepted sites for assessing core temperature differ with regard to varying amounts from this temperature. Esophageal and tympanic temperatures are essentially the same as the temperature of the pulmonary artery,^155,166 whereas rectal temperature averages about 0.4° C (0.7° F) higher, and axillary and oral temperatures are about 0.2° C (0.4° F) and 0.4° C (0.7° F) lower, respectively.^10,110,155

Although esophageal temperature is somewhat difficult to obtain, this is the site that is most likely to accurately reflect the temperature of the pulmonary artery. Measurement at this location accurately follows changes in core temperature and is reasonably noninvasive. For placement, the probe is lubricated, and a small amount of local anesthetic is applied. It is then passed via a nasal passage into the distal portion of the esophagus to the level of the heart. The probe can be moved up and down slightly to obtain the highest temperature. Although this procedure is routinely used in physiology experiments, it is somewhat unpleasant for conscious patients. Esophageal temperature is affected by swallowing for about 30 seconds.

Tympanic temperature as an estimation of core temperature has long been controversial. Because the tympanic membrane is highly vascular and supplied by branches of the external and internal carotid arteries, it should be an ideal site. Nevertheless, over the years many studies have indicated that tympanic temperature is affected by ambient temperature and local facial cooling.¹⁶⁶ Conditions under which these complications can be avoided have now been clarified: (1) if the ear canal is insulated; (2) if the thermocouple is made of fine wire and insulated except at the active junction; and (3) if the thermocouple is in direct contact with the tympanum (which causes the patient to “hear” a continuous and low-pitched sound), then alterations in core temperature are detected more rapidly than by an esophageal probe, are not affected by facial skin temperature, and are otherwise identical to esophageal temperature.¹⁶⁶ In fact, if these conditions are adhered to during facial fanning, tympanic temperature provides a better estimate of brain temperature than do measurements made in the esophagus or the rectum.¹¹⁵ Accurate results were also obtained when an insulated probe was used in conjunction with an optical sensor to detect infrared radiation from the tympanum.¹⁷⁴ Whether the conditions met in these carefully controlled studies can be duplicated in the field is unknown.

In steady-state conditions, rectal temperature is a good index of core temperature, and it can also be used to estimate brain temperature.²⁰⁴ However, when the heat content of the body or of the internal thermal compartments is in flux, rectal temperature changes more slowly than temperatures measured in other commonly used sites.¹⁵⁵ There is a thermal gradient along the rectum, so all measurements should be made at a standard depth; 4 cm is recommended.¹⁰ The higher temperatures recorded in this region may be caused by a combination of low perfusion rates, digestive reactions, and bacterial activity, but there is not clear evidence of this.¹¹¹ For assessing core temperature during outdoor exercise in the heat, the National Athletic Trainers’ Association recommends that only rectal temperature be used.²⁹

Oral temperature is an excellent index of core temperature, provided that the mouth is kept closed. The sublingual pocket is well perfused by blood flow, and responds quite rapidly to alterations in core temperature. Mastication, smoking, fluid intake, and mouth breathing can affect sublingual temperature; these should be avoided during the period that immediately precedes the measurement.^10,110,111 The use of an electronic thermometer with a rapidly responding sensor makes this measurement considerably more accurate and rapid than when it is performed with a mercury-in-glass thermometer.

Although axillary temperature does reflect core temperature, it has a number of negative characteristics and should be used only as a last resort. The axillary temperature is affected by local blood flow as well as by thermal and nonthermal sweating.¹⁰ Changes in core temperature are slow to affect the axillary temperature, and there is high interpatient variability.¹⁵⁵ However, this measurement has proved to be particularly useful for assessing core temperature in infants.^10,111

Estimating Mean Body Temperature

Mean body temperature (MBT) provides a mass-weighted average of body tissue temperature and thus can be related to the heat content of the entire body. For a severely hypothermic patient, MBT provides a way to gauge the potential fall in core temperature (afterdrop) after vessel dilation caused by rapid surface warming. Traditionally, estimates of MBT have been made with the use of a formula that combines mean skin temperature and core temperature. Recently, the validity of such estimates was evaluated for patients undergoing various procedures, including cardiac surgery during extracorporeal circulation; these studies included core temperatures as low as 18.5° C (65.3° F).¹⁰⁶ “Peripheral compartment temperatures were estimated using fourth-order regression and integration over volume from 18 intramuscular needle thermocouples, 9 skin temperatures, and ‘deep’ hand and foot temperatures.”¹⁰⁶ The authors concluded that the estimation of MBT from Burton’s original formula²³ “is generally accurate and precise.”¹⁰⁶ That formula is as follows:

Ramanathan¹⁵¹ found that a rough but reasonably accurate estimate of mean skin temperature could be provided by the temperature of the medial thigh, and that a very accurate estimate of mean skin temperature could be made by measuring and weighting the temperature of four skin sites as follows:

Conductive Heat Exchange

Heat transfer between objects that are in direct contact is called conduction (H_d). The direction of heat flow is always from the higher to the lower temperature. Because conduction involves a direct interaction (i.e., contact) between molecules, this type of heat transfer is minimal except under certain circumstances, such as when sitting on a cold rock with a little insulation. Under such conditions, the heat lost to the rock would be similar to that lost from the remainder of the body surface by radiation and convection. Adequate insulation should be placed under patients who are in contact with hot or cold substrates.¹²⁵ The equation that governs heat exchange by conduction is

where k is thermal conductivity; A is the area of contact; T_sk is the skin temperature; T_a is the ambient temperature; and L is the distance between the two surfaces.

The thermal conductivity of a number of substances is given in Table 4-1. Note that water has 25 times the conductivity of air but only one fifth that of granite. Muscle tissue has about twice the conductivity of fat tissue. The conduction of heat through a tissue is called thermal diffusivity. This expression is obtained by dividing the thermal conductivity by the product of the density and the specific heat. The specific heats of various substances are also given in Table 4-1. Water and muscle tissue, which consists mostly of water, have particularly high values. However, specific heats can be misleading, so the volumetric heat capacities are also listed in Table 4-1. Although the specific heat of water is four times that of air, it takes about 3500 times as much heat to raise the temperature of a given volume of water by 1° C (1.8° F) as it does to accomplish the same feat with a similar volume of air. For someone in the water, the consequence of these properties is that skin temperature is within 1° C (1.8° F) of water temperature, and heat transfer to or from the environment is greatly facilitated. In cool water during rest, skin blood flow is minimized as a result of peripheral vasoconstriction. Heat loss is importantly determined by the subcutaneous fat layer; an average-size fat person with 36% body fat by weight begins shivering at a water temperature of about 27° C (81° F), whereas a lean person with less than 10% body fat starts shivering at about 33° C (91° F).¹³⁵

Convective Heat Exchange

Convection (H_c) can be seen as the facilitation of conduction caused by the movement of molecules in a gas or liquid. This movement decreases the functional value of L, which is the denominator in the conduction equation. Convection can be either forced or natural (free). Forced convection results from gas or liquid movement caused by the application of an external force, such as the movement of a fan or the pumping of a heart. Natural convection results from density changes that are produced by heating or cooling molecules adjacent to the body. These density changes cause the molecules to move with respect to the body surface. For humans, natural convection predominates at air speeds of less than 0.2 m/sec (0.7 ft/sec), whereas forced convection is more important at greater air speeds.¹²⁴

The relationships that define heat exchange as a result of convection can be complicated. They depend on surface temperature profiles, surface shape, flow dynamics, density, conductivity, and specific heat. Any factor that impedes the movement of the boundary layer (i.e., the molecules immediately adjacent to the body) greatly retards convective heat transfer.

Brengelmann and Brown¹⁶ have noted that, under relatively neutral conditions (T_a = 29° C [84.2° F], wind velocity = 0.9 m/sec [3 ft/sec]), about 40% of heat loss from a nude human is mediated by convection. Increases in air or fluid velocity greatly increase convective heat transfer. Fanning a minimally clothed patient will greatly augment heat loss in a cool environment.

Radiative Heat Exchange

All objects at temperatures of more than absolute zero emit electromagnetic radiation. This energy transfer occurs through space and does not require an intervening medium. In any given situation, the object is both transmitting and receiving infrared thermal radiation. In some cases, the object also receives solar radiation. The net heat transfer depends on the absolute temperatures, nature of the surfaces involved, and solar input. Surfaces that are effective absorbers of radiation are also effective emitters of radiation. The idealized “black body” illustrates this property; such bodies absorb all and reflect none of the incident radiation. Conversely, poor absorbers (e.g., a polished silver surface) are also poor emitters. Heat transfer that results from infrared (first-term) and solar (second-term) radiation is given by the following equation:

where H_r is the radiative heat exchange; s is the Stefan-Boltzmann proportionality constant; e_sk is the emissivity of the skin; e_a is the emissivity of the environment; T_sk is the skin temperature (given in K); T_a is the ambient temperature (given in K); a is the absorptance; r is the reflectance; and s is the solar radiation.

For temperatures in the physiologic range and where (T_sk − T_a) is less than 20° C (68.0° F), several authors have noted that infrared radiation heat exchange is roughly proportional to T_sk − T_a.^14,168 Also of note is that the spectrum of emitted radiation depends on the temperature of the object. At physiologic temperatures, the predominant wavelengths of emitted radiation are longer (infrared), whereas, at higher temperatures (e.g., like that of the sun’s surface), the predominant wavelengths are shorter (visible radiation) and can be detected by the human eye. This difference leads to some important consequences. The middle infrared radiation that is emitted by mammals is maximal, regardless of skin pigmentation or the color of clothing. However, solar radiation peaks in the visible portion of the spectrum and is differentially absorbed. In other words, dark clothes absorb more heat from solar radiation than do light clothes, but both types emit similar amounts of radiation energy.

Incident radiation can vary drastically under different environmental conditions and may severely tax the body’s ability to respond. Heat input from solar radiation on a cloudless day may exceed by several times the heat produced by basal metabolism; on a cloudless night, there is a significant net loss of radiation to the sky. Under the relatively thermoneutral conditions noted earlier by Brengelmann and Brown,¹⁶ radiant heat loss accounts for about 45% of the total.

Peripheral Thermal Sensors

The entire outer surface of the body is well supplied with sensitive thermoreceptive structures. Because one destination of the output of these transducers is the sensory cortex, many properties of the receptors can be gleaned from direct experience. Afferent thermal information produces both hot and cold sensations, and it is particularly rate sensitive. In addition to cortical input that arrives via the medial lemniscus and the ventrobasal thalamus, the brain receives a large amount of thermal information from pathways that synapse in the reticular area.²⁰ Although cortical thermal input is part of the sensory information that is used to reconstruct the external thermal environment, reticular inputs are more important to the behavioral and autonomic regulation of body temperature.⁴³ This distinction was pointed out by Cabanac,²⁶ who found that internal body temperature determined whether a particular surface temperature was perceived as pleasant or unpleasant. However, altered body temperature did not affect the discriminative (cortically mediated) aspects of the thermal stimulus; subjects had no problem correctly identifying the actual peripheral temperature. This study also confirms the intimate relationship between the thermoregulatory network and the pleasure–pain system.¹⁴²

The structure, location, and properties of peripheral thermoreceptors are well documented. Thermal sensors are free nerve endings, and they are categorized as either warm or cold. Cold receptors are found immediately beneath the epidermis, whereas warm receptors are located slightly deeper in the dermis. The hallmark of both types of receptors is their extremely high rate sensitivity (Figure 4-3, online). Although the static firing rate of cold receptors is usually less than 10 impulses per second, under conditions of rapid temperature change, firing rates are often higher by an order of magnitude. Cold receptors are excited by cooling and inhibited by warming, and they have static maxima at about 25° C (77.0° F); these receptors are active from about 10° C (50.0° F) to 40° C (104.0° F). Warm receptors are excited by warming and inhibited by cooling, and they have static maxima at more than 40° C; they are active from about 30° C (86.0° F) to 45° C (113.0° F). At both ends of the spectrum, more extreme temperatures activate neuronal responses that are phenomenologically reported as “cold pain” and “warm pain.”⁷²

FIGURE 4-3 Impulses from a recording that includes a single warm fiber and a single cold fiber. A, In this recording, a shield was periodically placed in front of and then moved away from the skin site that was innervated by the warm fiber. The discharge stops immediately when the skin is shielded from the radiation source. B, In this recording, the shield was simultaneously placed in front of the skin site innervated by both the warm fiber and the cold fiber. This caused excitation of the cold fiber and inhibition of the warm fiber.

(From Hensel H, Kenshalo DR: Warm receptors in the nasal region of cats, J Physiol [Lond] 204:99, 1969.)

Recent work with the use of cloning and ion-channel characterization has elucidated peripheral temperature transduction mechanisms. A family of related temperature-activated transient receptor potential (TRP) ion channels is highly sensitive to temperature. The cloned receptors TRPV3 and TRPV4 respond over a range similar to that of the warm receptors just described, whereas TRPM8 responds similarly to the cool receptors. TRPM8 also responds to menthol, eucalyptol, and icillin.^117,146 TRPV1, TRPV2, and TRPA1 respond similarly to the heat-pain–sensitive and cold-pain–sensitive neurons. The heat-pain channels (vanilloid receptor 1 [VR1]) also respond to low pH, ethanol, and capsaicin, which is the active ingredient in chili peppers.¹⁴⁴ Alternatively, TRPM2, TRPM4, and TRPM5 respond to warm temperatures and involve insulin secretion¹⁸⁷ and taste.¹⁸³ However, they are not regarded as warm receptors for thermal sensation, because sensory neurons have none of those receptors. In addition to TRP channels, TREK-1 and TRAAK channels may also be related to control of warm and cold perception.¹³⁷

Psychophysical and physiologic studies indicate that thermal receptors are not uniformly distributed across the body surface and that there are far more cold receptors.⁷² Cold receptors are abundant in the face and trunk areas, especially in the lips; however, they are less numerous in the feet and lower legs. The face and fingers have a greater number of warm spots.^153,181 Threshold temperature for the perception of thermal sensation follows the anatomic distribution and is not uniform across the body. The face, particularly near the mouth, is exquisitely sensitive, whereas the extremities, by comparison, have poor sensitivity. Other regions of the body are intermediate in sensitivity.¹⁷⁹

Because peripheral thermal input is intimately involved in regulation of body temperature, heating and cooling different body sites can differentially affect the magnitude of the restorative physiologic response produced. In one study, cooling the forehead was found to be more than three times as effective (per unit area) for decreasing ongoing sweating as was cooling the lower leg.⁴¹ A separate study evaluated regional trunk and appendage sensitivity to cooling by assessing the magnitude of the gasping response that occurs at the onset of immersion. In this case, exposing various parts of the body to water at 15° C (59.0° F) indicated that the upper torso had the greatest cold receptor density or sensitivity (or both). The lower torso was somewhat less sensitive, with the arms and legs exhibiting similar but considerably lower sensitivity.²²

Central Thermal Sensors

Many sites within the body are capable of eliciting generalized thermoregulatory responses. Such areas include the abdominal viscera, spinal cord, hypothalamus, and lower portions of the brainstem.^12,69 The genesis of input to the regulator that results from heating or cooling these areas is poorly understood. Some of the effects may result from modulation of synaptic connections rather than from stimulation of specific thermodetectors per se. Input from central detectors is not rate sensitive; rather, it is a direct reflection of the absolute temperature. The area with the highest thermal sensitivity and that has received the greatest amount of experimental attention is the preoptic area/anterior hypothalamus (POAH). Heating or cooling this portion of the brainstem elicits the entire array of autonomic and behavioral heat loss and heat gain responses, respectively.⁶⁸ Neurons in this portion of the brain exhibit both warm sensitivity and cold sensitivity.¹² Recent work on hypothalamic slice preparations with the use of synaptic blockers has indicated that warm sensitivity may be an inherent property of some of the POAH neurons, whereas cold sensitivity in this area of the brain requires synaptic input.^12,45 Figure 4-4, online illustrates the effects of temperature on the firing rates of three representative types of hypothalamic neurons.

FIGURE 4-4 Effects of temperature on the activity of three different types of hypothalamic neurons. A, Low-slope temperature-insensitive neuron. B, Moderate-slope temperature-insensitive neuron. C, Warm-sensitive neuron. The thermosensitivity in each case was 0.06 (A), 0.5 (B), and 1.1 impulses s⁻¹ • ° C⁻¹ (C). All three types of neurons displayed depolarizing prepotentials, and action potentials occurred when the prepotentials reached threshold. As exemplified in C, putative postsynaptic potentials (especially inhibitory ones) were often observed in all neuronal types.

(From Griffin JD, Kaple ML, Chow AR, et al: Cellular mechanisms for neuronal thermosensitivity in the rat hypothalamus, J Physiol 492:231, 1996.)

The high level of temperature sensitivity shown by one of the cells (labeled “C”) results from the temperature-dependent characteristic of the prepotential. Voltage-clamp experiments indicate that the altered rate of depolarization is most likely the result of an effect on hyperpolarizing (K⁺) conductances.⁶⁴ Work involving the use of hypothalamic slices has also established that about one-half of the thermosensitive neurons also respond to nonthermal stimuli such as osmotic pressure, glucose concentration, and steroid hormone concentration. Such neurons could form the basis for the interactions between the homeostatic systems that are described later in this chapter. Figure 4-5, online illustrates the response of a warm-sensitive POAH neuron in a slice preparation. This cell is excited by increased temperature, low glucose, or increased osmotic pressure.¹³ TRPV protein expression has been detected in the POAH; thus, it was proposed that the TRPV channels may underlie the thermosensitivity found in POAH neurons¹⁴⁴ and that both TRPV1 and TRPV2 channels may be active within the physiologic range of temperature.^93,149 However, a large body of evidence is at odds with the proposal of TRPV1 as a thermosensor.¹⁵⁷ Furthermore, TRPV channels respond to warming with persistent inward cationic currents, and this would produce a change in the resting membrane potential. In the POAH, both warm-sensitive neurons and temperature-insensitive neurons show identical membrane potential responses to temperature change.²⁰³ In addition, several in vivo studies have shown that TRPV1, TRPV3, and TRPV4—all of which are expressed in the hypothalamus—are not likely to be involved in thermoregulation in either the heat or the cold.^31,107,118 It is more likely that POAH warm sensitivity is caused by brief ionic currents that determine the rate of change in depolarizing the prepotentials that occur between two successive action potentials.⁶⁴

FIGURE 4-5 The response of a warm-sensitive preoptic nucleus–anterior hypothalamic area neuron to changes in temperature, glucose concentration, and osmotic pressure. The large downward arrows indicate media changes.

(From Boulant JA, Silva NL: Neuronal sensitivities in preoptic tissue slices: Interactions among homeostatic systems, Brain Res Bull 20:871, 1988.)

Regulator

As mentioned previously, the brain is capable of accurately regulating body temperature under a wide range of conditions. Although almost all portions of the central nervous system can potentially be involved, the most critical neuroanatomic structures for thermoregulation include the spinal cord, brainstem, hypothalamus, and septum. The preoptic area and anterior hypothalamus are particularly important for both integration and sensing of internal temperature.^68,70 Recent advances in neurophysiologic and neuroanatomic techniques have been used to extend our understanding of the systems involved in regulation of body temperature; a number of excellent sources document this progress.^11,122,200 Notable advances include demonstration of the relative independence of populations of neurons that control separate effector systems^91,202 and elucidation of a pathway that conveys cold-sensitive afferent (feed-forward) information to the hypothalamus.¹³¹

A schematic model for regulation of body temperature is presented in Figure 4-6. Credit for much of the information and organization in the figure comes from the authors listed in the figure legend as well as from many others in the field. For ease of understanding, many aspects of the system’s complexity have been simplified or modified. Among the many inputs to this system that are not shown include those mentioned in the section about central thermoreceptors (e.g., glucose concentration, osmotic pressure) as well as factors that are covered later in this chapter (e.g., time of day, hormone levels, pyrogen titer, oxygen concentration of the blood). In addition, central thermoreceptors from many locations in the body provide input to this system.

FIGURE 4-6 A simplified schematic diagram of the basic parts of the nervous system responsible for regulating internal body temperature. Details of how this system functions are given in the text. ac, Anterior commissure; GLU, glutaminergic synapse; GABA, GABAergic synapse; oc, optic chiasm.

(Anatomic, neurophysiologic, and conceptual concepts represented in this image are from Boulant JA: Neuronal basis of Hammel’s model for set-point thermoregulation, J Appl Physiol 100:1347, 2006; Hammel HT: Regulation of internal body temperature, Annu Rev Physiol 30:641, 1968; and Morrison SF, Nakamura K, Madden CJ: Central control of thermogenesis in mammals, Exp Physiol 93:773, 2008. These articles should be consulted for a more rigorous explanation of the details of the thermoregulatory system.)

The key sensing elements of Figure 4-6 involve the peripheral warm and cold receptors and the central thermodetectors, the latter of which are depicted by solid cell bodies and bold axons. Peripheral input originates in the skin and enters the central nervous system via the spinal or trigeminal dorsal horns; this information ascends to both the midbrain and the thalamus. The thalamic neurons that receive thermal information project to the sensory cortex and subserve sensory integration and localization of peripheral thermal information. They are also likely involved to some degree in learned behavioral thermoregulatory responses.

Thermal afferent pathways reaching the midbrain are involved in the feed-forward aspect of regulation.¹³¹ Axons of the cell bodies in the midbrain synapse on cells in the midline subregion of the preoptic area. These preoptic cells receive excitatory input from peripheral warm and cold sensors, but they inhibit the cells upon which they synapse. The systems that subserve heat loss and cold defense act as if they reciprocally inhibit each other and receive output from a unitary integrating system. However, as mentioned previously, the systems are actually functionally separate to a large degree. In the schema of Figure 4-6, both systems depend on inherently warm-sensitive cells that have a high spontaneous firing rate at normal body temperatures. These cells inhibit the succeeding neurons, but the connections are such that, in a cold environment or when the body temperature is below normal, cold defense responses are disinhibited and heat loss responses are further suppressed. The opposite would occur in a warm environment or when the body becomes excessively hot.

The output of these systems under different conditions is illustrated in the panels below the neuroanatomic diagram of Figure 4-6. The middle panel illustrates the situation for a person with a body temperature of 37° C (98.6° F) in a thermoneutral environment. At 37° C (98.6° F), both systems are inhibited, and there is no effector response. If the body cools or becomes warmer, the inherently temperature-sensitive neurons disinhibit either the cold defense or the heat-loss system. The panel on the left illustrates the action of the feed-forward cold neurons in a cold environment. Although the inherently thermosensitive neurons do not change their firing rate as a result of a local temperature that stays constant, input from the peripheral cold-sensitive pathway disinhibits the cold defense system. A similar situation—but in reverse—occurs when a person encounters a warm environment; that situation is depicted in the right panel. The error signal or output driving force is shown as the difference between the horizontal dashed line and the effector output at a given body temperature. The system is extremely accurate, and the error signal created by peripheral feed-forward input is usually just sufficient to counteract the sensed disturbance and to maintain body temperature at a constant level.

In addition to autonomic responses that are organized and transmitted from the brainstem (e.g., sweating, shivering), various complex whole-animal responses are also activated by the thermoregulatory system. Postural reflexes (e.g., huddling, sprawling) and complex learned behavioral thermoregulatory responses are initiated by cold and warm error signals. Although the mechanism is not understood, appropriate behavior reduces the error signal and activates the reward system, which likely culminates in the release of dopamine in the nucleus accumbens of the septum via cell bodies located in the ventral midbrain.⁸¹

Vascular Adjustments

Excellent overviews of the role of the vasculature in coping with thermal stresses are available.^16,33 One function of the circulatory system is to maintain a relatively homogeneous internal body temperature. Heat from metabolically active organs is convectively distributed to portions of the body where less heat is produced. More commonly appreciated are alterations of blood flow patterns that increase or decrease the overall thermal conductivity of the body during exposure to hot or cold environments, respectively. Some of these alterations in conductivity result from the preferential shunting of peripheral blood flow superficial or deep relative to the subcutaneous fat layer. Indeed, fat has about one-half the tissue conductivity of muscle. Nevertheless, shunting blood away from major portions of the body is at least as important for determining overall conductivity as is the conductive property of the tissue itself. For example, during immersion in cold water, muscle accounts for about 90% of the total tissue insulation of the forearm.⁴⁸ Thus directing blood away from poorly insulated (and more highly conductive) regions reduces heat loss and preserves core temperature.

In addition to capillaries, microcirculatory units contain arterioles, metarterioles, and arteriovenous anastomoses. Flow through all of these vessels is under the control of smooth muscle. The smooth muscle of precapillary sphincters is largely influenced by local factors such as the partial pressures of oxygen and carbon dioxide, whereas the other vessels are well supplied with receptors that respond to both neuronal and endocrine inputs. Glabrous skin (i.e., the palms, lips, and soles) contains numerous arteriovenous anastomoses and is innervated only by sympathetic vasoconstrictor fibers. Nonglabrous (i.e., hairy) skin is innervated by sympathetic vasoconstrictor and vasodilator fibers and contains few arteriovenous anastomoses. The vasoconstrictor system acts primarily through α-1 and α-2 adrenoceptors. By contrast, the active vasodilator system makes use of acetylcholine. This was verified by experiments that involved intradermal injection of botulinum toxin, which blocks the release of acetylcholine.⁹⁶ However, in the same experiments, involvement of an unidentified cotransmitter was also suggested. Vasoactive intestinal polypeptide is a likely candidate, because nitric oxide is an important end product for inducing active vasodilation.⁶ About 90% of the elevation in skin blood flow during heat stress is a result of input from the active vasodilator system, and, of this, about 30% is the result of nitric oxide.⁶ Thermoregulatory skin blood flow can reach up to 8 L/min and involve 60% of the cardiac output.³³

Operation of the vasomotor effector system is affected by excessive exposure to ultraviolet B radiation. Moderate sunburn impairs the vasoconstrictor response to cold; an associated uncontrolled increase in thermal conduction is still present 1 week after exposure, although the original erythema will have disappeared.¹⁴⁰

Central Signal

Vascular changes are bioenergetically the least costly thermoregulatory autonomic effector response. Because of the high sensitivity of the vasomotor system, ambient temperatures between the thresholds for sweating and shivering are often referred to as being in the zone of vasomotor regulation. If a particular vascular bed is kept at a relatively constant temperature, output from the central nervous regulator can be assessed. Under these conditions in dogs, manipulations of hypothalamic temperature confirm a high level of vasomotor activity between the thresholds for the activation of panting and shivering.⁷¹ In humans, forearm blood flow increases rapidly as core temperature rises; a sixfold increase in blood flow can occur with a core temperature that has risen to only 38° C (100° F).¹⁹¹ Within the vasomotor zone (i.e., skin temperatures of 33° to 35° C [91.5° to 95.1° F]), core and skin temperatures linearly combine to control skin blood flow. Skin blood flow responds accurately and rapidly to changes in skin temperature, which leads to a very stable core temperature.¹⁷

Although most peripheral arterioles are well supplied with adrenergic receptors, output from the thermoregulatory centers is not homogeneously distributed. Extensive nervous inputs from the thermoregulator occur only in the lips, ears, and distal extremities; thus immersing the feet in cold water leads to marked vasoconstriction in the hands and forearms but not in the abdomen or upper arms.⁶³

Local Modulation

Local temperature has a great effect on the vasomotor status of the peripheral vessels, and, in some cases, may be largely responsible for the observed thermal conductivities. Local heating produces a biphasic response. Initial dilation occurs in a few minutes and depends on release of various factors from the nerve ending. The VR1 receptors mentioned previously are involved in this response. The longer-lasting second phase of dilation is not dependent on local nerve endings, and involves nitric oxide. Local cooling can decrease superficial cutaneous blood flow to almost zero.³³ Although vascular beds on the skin surface constrict in response to cooling, other vascular beds dilate when cooled.⁵¹ The specific response to cold shown by cutaneous vessels follows from the observed distribution and properties of the α-adrenergic vascular receptors. Although in most of the vasculature α₁-receptors predominate, in the superficial cutaneous areas, α₂-receptors constitute a clear majority. The usual predominance of α₁-receptors is found in the deeper blood vessels. Local temperature affects the α₂– and α₁-receptors in a reciprocal manner. Although cooling augments the response of the α₂-receptors, it either inhibits or does not affect the response of the α₁-receptors. Thus cooling the skin not only constricts the superficial vessels but also concomitantly dilates many underlying vessels. The ensuing flow pattern increases tissue insulation and augments countercurrent exchange between incoming cool blood and outgoing warm blood.^51,53 Although initial work was done on canine vessels, subsequent studies that involved α-adrenergic agonists and antagonists have demonstrated that a similar mechanism exists in human fingers.^49,52

The responsiveness of cutaneous blood vessels is diminished in people with type 2 diabetes mellitus. The increased incidence of this disorder among the general population presages a greater number of patients exhibiting severe hyperthermia.³³

Central Signal

By controlling the local milieu at different skin sites, it has been possible to separate the central thermoregulatory drive to sweat glands from local effects on the glands themselves. The central thermoregulatory system provides a proportional output that is influenced by both internal and whole-body skin temperatures. Per degree increase above thermoneutral values, internal temperature is about 10 times as important as is mean skin temperature for eliciting an output to the sweat glands.^126,128

Local Modulation

Local effects are also important for determining the output of sweat glands. Temperature exerts a multiplicative effect on sweat secretion; the Q₁₀ for this augmentation is about 3.70. In addition, skin wetness has an important local effect on sweat glands. The wetter the skin, the greater the suppression of sweating.¹²⁷

Moderate sunburn disrupts evaporative cooling. This effect is locally mediated and involves decreases in both responsiveness and capacity of the sweat glands.¹⁴¹

Central Signal

Of the various thermoregulatory outputs, metabolism is the easiest to evaluate quantitatively; the most complete documentation is available for this response, and most models of the thermoregulatory system are based on this information. Experiments on medium-size mammals have allowed for separate thermal manipulation of various parts of the brain, body core, and skin. This work has made it clear that the thermoregulatory centers act as a proportional controller and that skin temperature provides a feed-forward input to the system.^68,84 Thus greater decreases in either core or skin temperature or both below neutral values elicit proportionally larger compensatory increases in metabolism. In addition to an impaired ability to generate metabolic heat, hypothyroidism is also associated with a decrease in regulated core temperature of about 1° C (1.8° F).¹⁹⁶

Evidence indicates that humans have a control system similar to that of medium-sized mammals. In a summary of their data and of that collected previously, Hong and Nadel⁷⁷ noted that central output for shivering is augmented by increased rate of skin cooling. They also concluded that a given decrease in core temperature elicits 10 to 20 times the metabolic response of an equivalent decrease in mean skin temperature. Exercise is not incompatible with shivering, but increased levels of exercise exert increasing degrees of suppression on the shivering response, possibly as a consequence of an increased arousal response.⁷⁷

Local Modulation

Although the central and local effects of decreased core temperature on shivering have not been directly partitioned, both inputs are important. Slight decreases in core temperature create large compensatory responses, as delineated previously. However, even moderate hypothermia decreases the metabolic response to cold, and, at about 30° C (86.0° F), the shivering response is lost.¹⁶ This decrement must involve nervous system malfunction, because the muscles themselves are quite responsive below this temperature. For example, limb muscles and diaphragm muscles develop peak tensions that are not greatly affected by temperatures down to 25° C (77.1° F), and fatigue resistance is considerably increased at 25° C (77.1° F).^150,170 Likewise, altering the skin and superficial muscle temperature of the anterior thigh through a range of temperatures between 12° and 40° C (between 53.6° and 104.0° F) for 30 minutes had little effect on subsequent isometric peak torque production during isometric knee extensions to exhaustion. Time to fatigue was longer at the coolest temperature.¹⁸⁶

Central Signal

As compared with the knowledge about autonomic thermoregulation, we know little about the neural mechanisms that underlie behavioral thermoregulation. As noted in previous sections, the preoptic area plays a key role in autonomic thermoregulation. Animals with lesions of the POAH are severely compromised with regard to their ability to use autonomic thermoregulatory effectors; however, their ability to behaviorally thermoregulate is relatively intact.^28,164 These results indicate that the preoptic area is not as crucial for behavioral thermoregulatory processes as it is for autonomic processes.^27,163 Alternatively, lesions of the lateral hypothalamus, which is involved in various reward systems, result in the loss of behavioral thermoregulation.¹⁶⁵

Recent studies involving the use of positron emission tomography and functional magnetic resonance imaging have demonstrated that temperature signals from the body surface reach the insular cortex.^38,79,138 However, insular activation correlates with the discrimination between hot and cold rather than with thermal pleasure, so this system is likely minimally involved with behavioral thermoregulatory processes. Alternatively, thermal pleasantness is clearly important for behavioral thermoregulation. In studies involving functional magnetic resonance imaging, it has been shown that activation of the amygdala, mid-orbitofrontal and pregenual cingulate cortices, and striatum is correlated with thermally related pleasant and unpleasant feelings.^91,156

Because behavioral processes are usually activated before body core temperature changes via the feed-forward system, signals from the skin are important. However, severe deviations in core temperature disrupt this system. When this occurs, the person no longer feels too hot or too cold, and the desire to take corrective action is lost.

Regional differences in the contribution of the body surface to thermal comfort are present.¹³² Facial cooling produces the most pleasant experiences during mild heat exposure, whereas during cold exposure, local warming of the chest and abdomen leads to the most pleasant sensations. This would induce us to preferentially cool the head in the heat and to huddle or add clothing to warm the torso in the cold.

Local Modulation

As with shivering, most problems that involve behavioral temperature regulation probably emanate from disruption of centrally generated output. The muscles used to move the body are fairly resistant to thermal incapacitation, as described previously; however, if this occurs, a major disruption of the body’s thermal defense ensues.

Normal Variations in the Regulated Temperature and in the Ability to Maintain Body Temperature

The same body temperature can represent a different state of affairs even under regularly encountered circumstances. Some of these conditions are noted here.

Fever

Increased body temperatures have been associated with illnesses for thousands of years. On the basis of the population data presented previously, febrile body temperatures for resting young adults include morning temperatures that are equal to or that exceed 37.3° C (99.2° F), which increase gradually to 37.8° C (100.0° F) for early afternoon and evening. Such elevated temperature needs to reflect a regulated increase to be considered a true fever. Pathogens and cancers are the usual causes of such increases in the regulated temperature, but they are not directly responsible for the increased body temperature; rather they interact with components of the immune system such as macrophages, T cells, monocytes, and Kupffer cells as well as with glial, epithelial, and many other types of cells. This interaction stimulates the cells to produce pyrogenic cyotokines,¹¹³ including interleukin-1, interleukin-6, and macrophage inflammatory protein-1. Cytokines act on cells in the vicinity of the anterior hypothalamus and induce them to release prostaglandin E₂, which leads to an increase in the regulated temperature.¹⁰⁰ Important avenues by which cytokine-mediated pyrogenic signals reach the brain include peripheral inputs from the abdominal vagus nerve¹⁶⁰ and central inputs via the subfornical organs.¹⁸² Aspirin and related drugs block fever by inhibiting prostaglandin synthesis.¹⁰⁰ Interleukin-1 and other cytokines have many effects in addition to causing fever; these include decreased appetite, hypoferremia, activation of B and T lymphocytes, and increased slow-wave sleep.⁹⁹

The increase in body temperature during fever helps with many immune functions; neutrophil migration, release of reactive oxygen intermediates and nitric oxide by neutrophils, and interferon production are all augmented. It has been suggested that the most important aspect of fever is to greatly increase the temperatures of the peripheral tissues via selection of a warmer microclimate, addition of insulation, and postural changes. As peripheral temperatures increase from typical levels (i.e., 29° to 33° C [84.2° to 91.4° F]) to those that approximate core temperature, activation, proliferation, and effector production in peripheral cells involved in cell-mediated and humoral immunity are greatly increased and show temperature coefficients (Q₁₀) of 100 to 1000. By contrast, the Q₁₀ for the effectiveness of the newly created effectors themselves, as well as for antigen-nonspecific defense systems, are much lower at about 1.5 to 5.36.^100,101,161

The presence and beneficial effects of fever have been documented in a variety of cold- and warm-blooded vertebrates and even in some invertebrates. Under most conditions, it is probably not advisable to alleviate a fever. Exceptions include malignant hyperthermia and particularly high fevers during pregnancy.^100,101 In addition, for patients with limited fluid, oxygen transport, or cardiopulmonary reserves, a febrile response should be treated with antipyretics.⁹⁴ Consequences of the decreased immune response can be treated after the emergency.

Alcohol, Anesthetics, and Toxins

Increases in the blood concentrations of ethanol, anesthetics, and a number of toxic substances lead to substantial decreases in body temperature.^42,172 In many cases, this fall is caused by a decrease in the regulated temperature. In the case of high concentrations of alcohol and certain toxins, the reduction appears to be an adaptive adjustment that promotes survival. These chemicals disrupt protein structures within the cell membrane, and this effect is counteracted by a lower temperature.⁴² Indeed, mouse studies have shown that lowered body temperature counteracts ethanol toxicity.¹¹⁴ In humans as well, decrease in the regulated temperature is caused by increases in blood ethanol concentration. After ingestion of ethanol (3.0 mL/kg body weight) at 33° C (91.4° F), sweat rate increased and body temperature fell. Although skin temperature did not increase, subjects reported a warm sensation that paralleled the increase in sweat rate.¹⁹⁹ At 18° C (64.4° F), body temperature decreased continuously before and after the drinking of alcohol, with no facilitation of metabolic heat production. During this period, the thermal discomfort sensation became more intense, although the discrimination of cold per se was impaired after the ingestion of ethanol.^197,198 However, lower blood ethanol levels associated with moderate consumption in humans have minimal and inconsistent effects on thermal balance of the whole body.^46,86

Excellent overviews of the effects of general anesthetics on perioperative thermoregulation are available.^171,173 Many of these substances (e.g., halothane, fentanyl and nitrous oxide, enflurane, isoflurane) in anesthetic doses act in a similar manner. Heat-loss thresholds are increased by about 1° C (1.8° F), and heat-maintenance thresholds are lowered by approximately 2.5° C (4.5° F). Interestingly, in the typical clinical dose range, the gain (sensitivity) of the effector responses is nearly normal. In the conditions under which general anesthetics are normally administered, body temperature decreases significantly. An initial rapid drop is caused by redistribution of heat; cool blood from the periphery lowers central core temperature. A second and slower decrease results from a fall in body heat content. Finally, a plateau is reached, either because heat production and heat loss are passively balanced or because heat maintenance thresholds are reached. During postanesthetic recovery, there is vigorous shivering. Anesthetic-induced hypothermia is reduced in patients with higher preoperative systolic blood pressures. This difference is associated with higher preoperative plasma norepinephrine levels, which may intensify the vasoconstriction response.⁹² Cutaneous warming before and during anesthesia prevents the development of hypothermia and decreases the incidence of infectious complications.^103,171

Severe Hypoxia and Endotoxin Shock

When inspired oxygen concentration falls to 10% to 12%, a substantial decrease in the regulated temperature occurs. This reaction has been documented with the use of behavioral responses in fish, amphibians, reptiles, and mammals.^59,193 For humans who are exercising in 28° C (82.4° F) water under eucapnic conditions, decreasing inspired oxygen to 12% lowers the core temperature thresholds for vasoconstriction and shivering and increases the rate of core cooling by 33%.⁸⁷ The value of the resultant lowered body temperature is clear: the affinity of hemoglobin for oxygen is increased, and overall metabolic rate is decreased. The mechanism underlying the change in the regulated temperature may involve differential sensitivities of central neurons; hypoxia specifically increases activity of warm-sensitive neurons in the POAH.¹⁸⁴

A somewhat similar regulated hypothermic response occurs when an animal is exposed to very high levels of pyrogens; the same response occurs under less extreme conditions in weak or malnourished animals. The lowered body temperature may serve to decrease the energy costs of maintaining a high body temperature for a severely compromised animal.¹⁵⁹

Altered System Responsiveness and Capacities

A number of situations alter responsiveness of the thermoregulatory system. Awareness of these conditions is important when assessing the thermoregulatory capabilities of a particular person and when determining possible causes for hyperthermia or hypothermia.

Thermal Acclimation

Thermoregulation is affected by chronic exposure to very cold or hot environments as well as by chronic exercise in cool or warm ambient temperatures. Such exercise in a cool environment greatly increases responsiveness of the sweat glands; if exercise is in the heat, the central temperature at which sweating is initiated is also lowered. The net consequence of these adjustments is that a heat- and exercise-acclimated individual can workout at a given level with far less increase in core temperature.¹²⁹ Exercise in humid heat appears to decrease resting core temperature in acclimated individuals.¹⁴⁵ Increases in both core and skin temperatures contribute to various changes involved in heat acclimation.¹⁵² Physical training also increases skin blood flow at any given increase in core temperature.⁸⁵ Although acclimation to warm conditions produces many changes in the cardiovascular system, the basic baroreflex responses are not altered.¹⁹⁵

Heat acclimation may result in protective cellular adaptations. Intracellular heat shock protein 72 is likely involved in the maintenance of cellular protein conformation and homeostasis during hyperthermia, inflammation, and injury.¹²³ A 10-day heat- and exercise-acclimation test increased heat shock protein 72 levels in peripheral blood mononuclear cells.¹⁹⁴

Chronic cold exposure alters many thermoregulatory systems and involves long-term evolutionary changes and thermal acclimation. In many cases, resting metabolic rate is increased after repeated cold exposure;^20,204 however, repeated exposure to very cold environments may produce the opposite effect. For example, eighty 30-minute sessions at 5° C (41° F) decreased the metabolic response to a standard cold-air test and often led to lower internal temperatures in these cold-acclimated individuals.⁷⁴

When the extremities are initially exposed to cold, strong vasoconstriction is seen. At some point, however, cold-induced removal of the superficial α-receptor inhibition leads to vasodilation of the fingers, which warms the extremities and protects against frostbite. This response has a genetic component; for individuals who are not cold acclimated, this response is very strong among Inuit Eskimos, moderate among whites, and minimal among Chinese from Hong Kong. Individual differences in the vasodilation response to cold determine the relative likelihood of the development of frostbite. An environmental influence in this response is also likely; fishermen in northeastern Canada did not exhibit vasoconstriction of the fingers when exposed to cold.⁶³

Competition with Other Homeostatic Systems

In addition to a constant core temperature, the body has many other requirements. When fluid balance or energy requirements are not met, thermoregulatory responses can be compromised. For heat production and heat conservation, an adequate energy supply, patent nervous system, and functional effector organs are critical. Thus, hypoglycemia decreases the core temperature at which shivering is initiated while leaving the thresholds for sweating and vasodilation unaffected.¹⁴³

During exercise, heat is generated by activity of the muscles. About 80% of the energy consumption is converted into heat, with only about 20% going to the actual work produced by contraction of the muscles. High muscle temperature increases efficiency of muscle contraction.^7,8 However, an excessive rise in body temperature impairs endurance performance. It is well appreciated that 40° C (104° F) is very near the upper limit of core body temperature when trying to maintain prolonged exercise. The time to exhaustion during heavy exercise is affected by the initial body temperature.^61,134,136 In a heat-acclimation study, subjects exercised until exhaustion at 60% of their maximum for 9 to 12 consecutive days at 40° C (104° F).¹³⁶ The time to exhaustion became progressively longer with acclimation, but core temperature at the time of exhaustion remained at about 40° C (104° F). When body temperature was altered by water immersion before bicycle ergometer exercise at 40° C (104° F), time to exhaustion became progressively longer as initial body temperature was progressively lowered. Again, body temperature at exhaustion remained at about 40° C (104° F).⁶¹

For the maintenance of exercise performance and body temperature in a warm environment, body water status is critical.^121,167 It is common for a person who is working in the heat to lose 1 L of water per hour. Even when fluids are readily available, maintaining a euhydrated state may be difficult. For hypohydration during continued activity, each percent decrease in body weight leads to a core temperature increase of about 0.15° C (0.27° F). This decreased heat dissipation is mediated by two mechanisms. At a given core temperature, hypertonicity decreases the sweating response, and hypovolemia reduces skin blood flow.¹⁶⁷ Hyperhydration has no effect on thermoregulation during compensable exercise heat stress.¹⁰⁴ During uncompensable exercise heat stress, hyperhydration slightly increases the time to exhaustion but only by delaying hypohydration; thermoregulation is not affected.¹⁰⁵ It is important to be alert to the possibility of dehydration in many atypical situations. For example, swimmers training in an outdoor pool with a water temperature of 26° C (78.8° F) lost sufficient fluid (i.e., 2.5% of their body weight) in 3 hours to compromise thermoregulatory responses.¹⁷⁶

Hypoxia can undermine thermoregulatory vascular responses because of demands that compete or operate at cross-purposes. Thus, in a hot environment, hypoxia reduces skin blood flow at a given sweat rate. In the cold, hypoxia enhances core cooling by delaying the onset of vasoconstriction and cooling.¹¹⁹

Alcohol, Drugs, Anesthetics, and Toxins

Although moderate doses of anesthetics and toxins may elicit adaptive changes in a regulated body temperature, elevated doses of these substances impair or abolish both autonomic and behavioral aspects of thermoregulation. Body temperature then changes passively, depending on the thermal environment. This can be particularly dangerous when elevated levels of alcohol or similar substances are combined with heat stress. Impaired ability to dissipate heat is then combined with the enhanced toxicity of increased tissue temperature. Drugs that increase metabolic heat production (e.g., amphetamines, ecstasy [3,4-methylenedioxymethamphetamine], cocaine) are also particularly dangerous to use in the heat. In addition, cocaine interferes with heat dissipation mechanisms and with the perception of warmth.^19,39