Thermoregulation

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Chapter 4 Thermoregulation

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A warm body has long been recognized as one of the primary conditions of life. Although humans have physiologic, intellectual, and cultural capabilities that equip them to maintain viable body temperatures under many climatic conditions, thermal extremes, heavy exercise, and injury can rapidly lead to dangerous internal temperatures. For a physician who is operating in primitive circumstances, maintaining or restoring a patient’s body temperature can require quick action and ingenuity, both of which are aided by an understanding of the physiology of temperature regulation.

Because the thermal environment can be extremely complicated and the thermoregulatory system of humans is complex, making decisions about body temperature maintenance in the field can be difficult. This chapter is designed to aid in the decision process by providing a basic understanding of the relationships among the ambient thermal environment, the thermal characteristics of the body, and the thermoregulatory system. First, some overall concepts of temperature regulation as well as a way to conceptualize the system will be reviewed. Second, the range of normal body temperatures will be covered, along with the consequences of higher and lower body temperatures. Third, methods and potential pitfalls of monitoring body temperature will be outlined, after which the physical factors that affect heat flow will be covered. Fourth, the neuronal systems involved in processing thermal information (i.e., sensation, integration, and output) will be reviewed, followed by a detailed description of the effector organ responses involved in the maintenance of thermal homeostasis. Last, modifications of thermoregulatory responses, induced alterations of the regulated temperature, and changes in the responsiveness as well as in the capabilities of the thermoregulatory system will be noted. Note that, when values are given for “a person,” they refer to a 70-kg (154-lb) man.

Conceptualizing the Thermoregulatory System

Humans are homeotherms and as such are capable of maintaining a relatively constant body temperature across a wide range of ambient temperatures. Such constancy is attained through the use of behavioral processes that involve maintaining or searching for a preferable environment and autonomic processes such as vasodilation of the skin blood vessels and sweating in the heat and shivering in the cold. These processes are controlled via a negative feedback system with a primary feed-forward input from skin sensors that monitor ambient temperature (Figure 4-1).89 The feed-forward input from the skin allows for the elicitation of thermoregulatory responses without a change in core body temperature. Thus, the primary regulated variable, core temperature, can remain relatively constant under widely varying environmental conditions. Without the feed-forward element, if a hot or cold stress were encountered, large amounts of heat would be gained or lost before deep body sensors were sufficiently affected to elicit restorative responses. In addition, when greater thermal stresses were encountered, greater deviations in core temperature would be necessary to elicit sufficient restorative responses.

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FIGURE 4-1 A negative feedback system with feed-forward input from the main disturbance (ambient temperature), which decreases variation of the main regulated variable (core temperature).

(From Kanosue K, Crawshaw LI, Nagashima K, et al: Concepts to utilize in describing thermoregulation and neurophysiological evidence for how the system works, Eur J Appl Physiol 109:5, 2010.)

Figure 4-2 illustrates some of the concepts that relate to the thermoregulatory system and that will be discussed in this chapter. Under normal conditions, body temperature is relatively constant under a range of ambient temperatures, as is depicted by trace “a.” The breadth of this range of ambient temperature is called the range of normothermia. The midpoint of this range can be conveniently called the regulated temperature, which is shown by the dot in trace “a.” Toward the upper and lower ends of trace “a,” the core temperature inflects up and down. These inflections represent ambient temperature extremes at which the regulation begins to fail. Altered core temperatures can also accrue when there are alterations in the regulated temperature. Such alterations could be caused by the presence of bacterial toxins (e.g., fever) or starvation, which would cause increases (trace “b”) or decreases (trace “c”) in the regulated temperature. In addition, under various conditions, the effector responses can become compromised, which leads to decreases in the ability to defend against low temperatures (dashed line at “d”), which could indicate a problem with metabolic stores, or high temperatures (dashed line at “e”), which may indicate dehydration. Of course, various combinations of regulatory changes and altered effector responsiveness occur in conjunction with many threatening situations.

Basics of Core Temperature

Typical measurements of core temperature provide a good estimate of the temperature of critical internal organs and are quite stable across individuals. In a study that involved 700 observations of 148 healthy individuals,113 90% of the early-morning oral core-temperature measurements were between 36.0° C (96.9° F) and 37.1° C (98.9° F). Core temperature is vigorously defended by the body. At low temperatures, regional heterothermy that results from peripheral vasoconstriction forms an important aspect of this defense. The lowered skin temperature decreases the thermal gradient from the skin to the environment and thus decreases heat loss. At cooler temperatures, there can be a large amount of peripheral tissue that is well below core temperature, which leads to a major decrease in the overall heat content of the body. A nude human resting at 35° C (95° F) or 20° C (68° F) exhibits similar temperatures at various locations within the core. However, because of decreased temperatures in the outer shell, a person resting at 20° C will have a total heat content that is about 200 kcal lower than when resting at 35° C.168 If the peripheral vessels were suddenly dilated, an immediate drop in core temperature of about 3.5° C (6.3° F) would result. In a hypothermic individual, the discrepancy between core and shell temperatures could be considerably greater and could result in a dangerous postdilation drop in core temperature. A method for making a rough estimate of the potential drop in core temperature after peripheral vessel dilation is given in Estimating Mean Body Temperature, later.

A different type of heterothermy may be present in hyperthermic humans. As the brain temperature reaches high levels, blood flow that normally moves outward from the intracranium to the face via the ophthalmic vein is redirected and flows from the face inward.75 This results in the brain being cooled by blood that has passed through areas that have been cooled by facial sweating and leads to a brain temperature that is lower than that of the remainder of the core. Although brain cooling is clearly documented and accepted in many mammals,5 there has been some controversy about its importance in humans.15,24 Nevertheless, there is unanimous agreement that the head is an extremely important area for heat loss.15,25 Thus, for hyperthermic patients, it is important to optimize the heat loss from that region and, when necessary, to augment cranial heat dissipation by fanning and moistening.

A variety of conditions can lead to an abnormal core temperature. Under some circumstances, the regulator may be defending an altered core temperature for reasons that will be described later in this chapter. Alternatively, the thermal load posed by the environment or by heavy exercise may be too great for the capacity of the effectors. Finally, the regulator could be deranged as a result of substance abuse, extreme temperatures, side effects of prescription drugs, or other factors. When interpreting a particular core temperature, it is important to evaluate all of these alternatives. Accidents in the wilderness often involve the compromise of many aspects of thermal balance, and an altered body temperature is very likely.

Consequences of Altered Core Temperature

When tissue temperatures change, there are immediate and important effects on metabolism as well as on other physiologic mechanisms. With a 10° C (18° F) increase in temperature, the metabolism of typical human tissue increases by a factor (Q10) of about 2.7. The metabolic rate of the entire organism—apart from thermoregulatory responses—responds similarly. For temperature differences other than 10° C (18° F), these effects can be calculated with the following equation:168

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where R2 and R1 are the two rates of physiologic response; T2 and T1 are the two temperatures; and Q10 is the increase in rate caused by a 10° C (18° F) increase in temperature.

Within the normal range of body temperatures, higher temperatures favor speed at the expense of tissue resources, whereas lower temperatures conserve resources. Although both high and low temperature extremes pose a threat to humans, increased temperatures greatly accelerate the development of serious complications and pose a much more immediate danger. A deviation of about 2° C (3.6° F) above or below normal core temperature is well tolerated by the various regulatory systems of the body, but a discrepancy of 3° C (5.4° F) begins to disrupt these systems, including those involved in temperature regulation. At this level of deviation, if there is no intervention, physiologic problems compound very rapidly.

A core temperature of 34° to 36° C (93.2° to 96.9° F) disrupts many important physiologic functions, which, taken together, may significantly affect patient outcome. Such mild hypothermia impairs recovery from surgical procedures as a result of such things as impaired peripheral blood flow and oxygen availability, increased possibility of cardiovascular complications, decreased antibody and cellular immune defenses, impaired coagulation, and increased metabolic expenditure for heat production.47,57,103,107 In most situations, it is very important to maintain the patient at normothermic levels.

Traumatic brain injury can be present in wilderness accidents, and it may be accompanied by hyperthermia. Heightened temperatures can exacerbate cerebral inflammation and lead to increased neuronal damage.185 There is current interest in invoking mild hypothermia to minimize damage to the central nervous system after neurologic injury.139 However, when this approach is used, care must be taken to deal with the side effects mentioned previously.148

Monitoring the Temperature of the Core and Other Sites

The overall status of the thermoregulatory system is determined by measuring the core temperature. This can be done at a number of sites with several types of instruments (i.e., thermometers). In the following paragraphs, the relative merits of locations and instruments are discussed.

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:

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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:

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Physical Factors That Govern Heat Exchange: The Heat Balance Equation

The physical laws that govern heat transfer determine the net energy flux into or out of the body.* The heat balance equation is a convenient method for partitioning and quantifying the flow of energy between the environment and the body. A high rate of metabolic heat production is critical for maintaining a constant body temperature in mammals. This is represented by total heat production (Htot) on the left side of the following equation. For a person whose body is at thermal equilibrium, the equation is balanced and given as follows:

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where Htot is the total metabolic heat production; Hd is the conductive heat exchange; Hc is the convective heat exchange; Hr is the radiative heat exchange; and He is the evaporative heat exchange.

Htot is always positive. The various modes of heat exchange from the right side of the equation can be positive or negative, depending on the situation. Positive values refer to net heat loss from the body. If the equation does not balance, the body either loses or gains heat. When the sum of the net heat exchange through the various channels exceeds Htot, heat content of the body will decrease, and mean body temperature will fall. Alternatively, if Htot is greater than the net heat exchange, heat content of the body will increase, and mean body temperature will rise.

Conductive Heat Exchange

Heat transfer between objects that are in direct contact is called conduction (Hd). 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

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where k is thermal conductivity; A is the area of contact; Tsk is the skin temperature; Ta 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 (Hc) 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 (Ta = 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:

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where Hr is the radiative heat exchange; s is the Stefan-Boltzmann proportionality constant; esk is the emissivity of the skin; ea is the emissivity of the environment; Tsk is the skin temperature (given in K); Ta 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 (Tsk − Ta) is less than 20° C (68.0° F), several authors have noted that infrared radiation heat exchange is roughly proportional to Tsk − Ta.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.

Evaporative Heat Exchange

When water changes state, a large amount of energy is either absorbed or given off. Evaporation of 1 g (0.035 oz) of water at 35° C (95.0° F), which is the usual skin temperature of a person who is sweating,168 requires the input of 0.58 kcal of thermal energy. In the field, the preferred cooling measure is to splash water on the patient, and this is coupled with air fanning.66 Heat absorbed by the evaporation of 100 cc of water will lower body temperature by about 1° C (1.8° F). In a neutral thermal environment, sweating does not occur, and evaporation accounts for only 15% of the total heat loss. Of this, slightly more than one-half is the result of evaporation from the respiratory tract, with the remainder coming from water that passively diffuses through the skin and evaporates.16

Although it is unusual, the evaporation term (He) of the heat balance equation can become negative, which means that heat is being introduced into the body. This occurs during airway rewarming, when water-saturated oxygen is introduced into the respiratory system at about 43° C (109.4° F). Because the victim’s body is considerably colder than 43° C, water condenses in the airways. For every gram of liquid water that is formed, the body heat content increases by 0.58 kcal.

Thermoregulatory Network

A regulatory system requires sensing the controlled variable, comparing it with an ideal value, and producing an appropriate output signal. In the following sections, the role of the nervous system in maintenance of a stable body temperature is outlined.

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

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.

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

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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.)

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