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Induced by Central and Peripheral Sensors in Human Thermoregulation C H A R L E S E . H U C K A B A , J O H N A . D O W N E Y , and R O B E R T C . D A R L I N G Department of Rehabilitation Medicine, College of Physicians & Surgeons, Columbia University, New York, Ν. Y. 10032
Engineering control concepts have been used to develop a comprehensive mechanism for human thermoregulation. Ex isting physiological evidence is accounted for by a feedback response induced by central sensors and feedforward antici patory action generated by peripheral signals. The manner in which peripheral effects either can reinforce or inhibit the action of the central sensors is explained. A unique study procedure, using patients with spinal cord transactions, per mits the proportioning of the total observed thermoregula tory response between the central and peripheral sensors respectively. These data provide the basis for evaluating the validity of mathematical functions proposed to represent the control elements under various physiological states and environmental conditions.
' t h e r m o r e g u l a t i o n i n mammals has been the subject of widespread investigation for many years. Because of the many animal species and the almost limitless combinations of environmental and physiological conditions under which temperature regulation is of interest, the literature i n this field is extremely broad and diverse. M u c h of the previous work has been conducted on animals, often studied under anesthesia, even though anesthetic agents can grossly dis tort thermoregulatory response. Moreover, there are marked differences in some of the basic modes of thermal compensation between animals and man—in an attempt to relieve an excessive heat load, for instance, some mammals including man sweat, whereas others such as the dog pant. Animal studies can be valuable i n developing general concepts, 256
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but quantitatively precise, reliable data regarding human thermoregu lation can be obtained only from studies on human subjects although such studies are subject to obvious constraints. Recent reviews of thermoregulation by Hammel ( J ) , Hardy (2), Downey and Darling (3), and Bligh (4), as well as a recent comprehen sive compendium of papers edited by Hardy et al. (S) have helped to form a critical assessment of the present status of work i n this field. Most of the work reported i n the physiological literature has been experimen tal, and only during the past decade has any concerted attempt been made to interpret the data in view of postulated control mechanisms. A n increasing number of papers are now appearing in which attention is directed to the possibilities of developing mechanisms which embody the basic concepts of engineering control theory. The manner in which the human body controls temperature is important not only under normal conditions but also during exercise, fever, and trauma induced by injury, burns, surgery, etc. Over longer periods of time, hormones, adaptation, and acclimatization can exert sig nificant effects. Although the work reported here is limited to normal short-term regulation, it is possible that the other situations can be explained in terms of modifications of the basic mechanism. Control
Mechanism
There is evidence that thermal sensors are distributed throughout the body. In animals sensors have been reported in the heart of the rabbit (6), the pulmonary vessels of sheep (7), and the spinal cord of the dog (8). However, it is agreed that some of the most important thermal receptors in the human are found in the anterior hypothalamus and the skin. The sensors at either of these locations can initiate thermo regulatory responses, and it is important that the action generated by each type of sensor be evaluated. However, most studies reported pre viously reflect the total response induced by both of these sources of sensory input acting together. There have been several attempts (9,10,11,12) to represent thermo regulatory action in a manner analogous to engineering control systems. For instance, the most frequent representation is the feedback loop, based on a hypothalamic temperature set point, which is the normal tempera ture ( 3 7 ° C ) for the central part of the body under ordinary circumstances. Figure 1 shows i n physiological terms the various elements of a conven tional feedback control loop for sweating. Although this mechanism for representing central effects has not been proved, there is evidence which suggests that it is appropriate for use as a working postulate.
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Several writers (10-13) have postulated a skin temperature set point, perhaps based on an average skin temperature which operates independ ently of that of the central hypothalamic temperature. However, since the skin is constantly exposed to a changing ambient temperature and since all parts of the body are i n continuous thermal communication with one another, i t is difficult to conceive that there is more than one inde pendent set point serving as the objective of the human temperature control system. Once the set point for hypothalamic temperature is specified, all other temperatures throughout the body are dependent. If the body were to attempt to control simultaneously the central tem perature to its set point and also some skin temperature to a second independent set point, the two control actions would be i n conflict and an oscillatory, unstable situation would develop. Since human thermo regulation, even in the face of drastic changes i n environmental tempera ture, occurs smoothly and at most with only minor instabilities, the evidence conclusively points to there being only the one central tem perature set point. Moreover, this set point is appropriately located i n the brain since this tissue should be given priority i n protection against thermal damage. To avoid the difficulties i n using the same mechanism for skin tem peratures as has been shown i n Figure 1 for the central sensors, another type of control loop is postulated for the peripheral effects. There are several instances i n the engineering field where a feedforward, anticipa tory control action must be used to achieve precise specifications. Because of their location on the surface of the body i n direct contact w i t h the environment, it is logical for the skin sensors to serve such an anticipatory, "early warning" function. T o visualize the basic action, i n the absence of a skin temperature set point, one must look for an alternative activation potential that would serve the same purpose as an error signal. There is physiological evidence (14) that the thermal sensors located i n the skin, although exhibiting some response as a function of static temperature Summer
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level, are activated primarily b y rate of temperature change. W a r m sensors and cold sensors are differentiated b y whether they are activated by a rising or falling temperature. T h e magnitude of the firing frequency of these sensors seems to be almost directly proportional to the rate of change of skin temperature. In view of this information, a feedforward control loop to account for the action generated by the peripheral sensors is shown i n Figure 2, again using sweating for purposes of illustration. Except for the fact that there is no set point, and thus no need for a comparator to generate an error signal, the elements i n this feedforward loop correspond exactly to those shown i n Figure 1 for the feedback loop.
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Even though we may account for the separate thermoregulatory responses which can be generated b y either the skin sensors or the central sensors, there still remains the task of showing how the two loops are combined to produce a coordinated control action. Our attempt at formu lating an overall mechanism is shown i n Figure 3. This signal-flow dia gram is comprised of a feedback loop and a feedforward loop for each of the three modes of thermal compensation: metabolic, vasomotor, and sudomotor. F o r the latter case the elements of Figures 1 and 2 are easily recognized i n the overall mechanism, and metabolic and vasomotor actions are represented by analogous loops. The signal modifier and summer combines the motivating potential produced b y the central sensors i n the form of an error signal based on the hypothalamic temperature set point with that generated b y the peripheral sensors. Since this signal processing element is i n continuous communication with each of the three controllers, it is possible, for i n stance, to activate a cooling response while inhibiting a heating response and vice versa. Moreover, the peripheral sensors can reinforce, attenuate, or even override a response being called for b y the central sensors, depending upon environmental changes.
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Figure 3.
Human thermoregulation: normal short-term control
Physiological evidence (15) indicates that the vasomotor controller responds to even minor signals and thus can effect small adjustments i n thermal balance. W h e n the vasomotor action is unable to achieve the required compensation, the appropriate major control action, either metabolic or sudomotor, comes into play. Moreover, to prevent their needless activation b y minor signals these controllers are protected by dead bands. Although the skin temperature, T i n comparison with dT /dt, may play only a minor role i n the activation of response mechanisms, it may well exert a significant effect on the dead bands of the metabolic and sudomotor controllers. Moreover, there is increasing evidence ( I , 5) that T exerts local influences on the magnitude of the response of peripheral blood vessels and sweat glands. Whereas skin temperature effects have been elucidated for various animals ( I , 4 ) , further work is needed to define these effects quantitatively i n the clinical human situation. F o r this reason i n the signal-flow diagram (Figure 3) T is shown as being available but not specifically committed with respect to definite points of interaction. 8y
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There is evidence i n the recent physiological literature which sup ports the postulated mechanism. Brown and Brengelmann (16) obtained data from water-bath studies which indicate that rate of change of skin temperature, dT /dt, is an important input which interacts with T and T to determine metabolic rate. They also concluded that magnitude 8
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and direction (i.e., whether + or — ) of dT /dt seem important and that this dynamic factor may exceed the steady-state contribution of T . Data from these experiments show that a negative dT /dt increases metabolic rate above steady-state levels and a positive dT /dt decreases metabolic rate. Bullard et al (12), Banerjee et ah (17), and Nadel and Cunningham (18) i n recent papers have emphasized the necessity of accounting for dynamic effects i n studying rates of sweating. The most dramatic demon stration of the influence of dTJdt on sweating has been reported by Wurster and M c C o o k (19). During a series of studies on ten male sub jects they observed inhibition of sweating after transfer of subjects from hot to cool environments. This inhibition occurred while central core temperatures were rising and skin temperatures were falling. The role of the central temperature-sensitive structures i n human thermoregulation has been the subject of intensive study b y many i n vestigators as reviewed by Hammel ( I ) . Downey et al. (20, 21) ob tained evidence that central cooling alone can initiate increased metabo lism and shivering even when the sentient skin is kept above 34 °C, which contradicts the conclusions of a previous investigator (22). There seems to be a consensus among workers i n this field that the action elicited by central sensors can be approximated adequately by the feed back mechanism shown i n our signal-flow diagram. F o r this reason it seems that attention should be directed for the present toward obtaining data for testing the feedforward loop as activated b y the peripheral sensors. 8
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Experimental
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Studies designed specifically to provide data for testing our proposed feedforward-feedback mechanism for human thermoregulation are i n progress. The greatest need is to obtain information on the individual responses which can be elicited by either the peripheral sensors or the central sensors acting alone. Figure 4, showing one of our studies, is typical of the data on metabolic response found i n the literature in which central and peripheral sensors fall simultaneously to produce a total com bined oxygen response. It is impossible to determine from a plot of this type how much of the increase i n oxygen consumption to attribute to the falling central temperature (T ) and how much was generated b y the falling skin temperatures. This difficulty has been overcome i n our studies b y using patients with spinal cord transsections, as described b y Downey et al (21), i n which the insentient portion of the body is used as a heat exchanger. W h i l e the sentient upper portion of the body is exposed to a falling ambient temperature, an equivalent amount of heat e&r
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is introduced into the insentient lower area by means of a surgical blanket. B y this method it is possible to maintain a constant ear temperature while the skin temperatures fall. Oxygen consumption is measured by an open circuit technique (21), and thermocouples are used to indicate temperatures of the ear, mouth, rectum, nine skin locations and at multiple points i n the environment. H a n d blood flow is measured using a waterfilled plethysmograph (23). Figure 5 shows the oxygen response resulting from skin cooling alone which was obtained i n a study on a patient with a T-10 lesion. I n this instance the patient was subjected to a step change i n ambient tempera ture by moving him quickly from a room at 30° C to a second room at 5 ° C . The curve shown for the anterior shoulder was typical of the rapid fall i n skin temperatures. T h e ear temperature was maintained constant, 37
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using the techniques described above, so that the entire oxygen response can be attributed to the change i n skin temperature. Figure 6 shows the results of a two-part study i n which, first, the ear temperature was maintained constant while the skin temperatures fell, and after 58 min the heating of the lower portion of the body was discontinued to permit the central (ear) temperature also to fall. This plot shows that a 3 5 % increase i n oxygen consumption was obtained by skin cooling alone and was further increased to 142% when the ear temperature was also allowed to fall. In terms of the proposed mechaism these results can be interpreted first as the response which was gen erated b y the feedforward loop, followed b y the enhancement caused by the activation also of the feedback loop.
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The time sequence of initiation of vasomotor and metabolic responses is significant to the postulated mechanism. Figure 7 shows that vaso constriction (reduced hand blood flow) has been completed before oxygen response starts. Moreover, the vasomotor response starts almost immediately upon application of a thermal stimulus. The dynamic effects of thermal stimuli are also seen i n this plot as oxygen consumption and hand blood flow follow the ambient temperature variation. %
Discussion The proposed control mechanism for human thermoregulation as represented i n Figure 3 b y the signal-flow diagram seems to accommodate
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presently available physiological evidence. A t the same time this com bined feedforward-feedback configuration agrees with the established engineering methodology where precise control specifications must be met. The data from our patient studies corroborate our postulated mech anism. These results, along with those reported b y other investigators, supply evidence of the importance of evaluating under dynamic condi tions the separate response which can be induced by central and periph eral sensors respectively.
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