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Thermoregulation and Fever in Normal Persons and in Those With Spinal Cord Injuries

      Thermoregulation and fever are primarily mediated through the hypothalamus and its effector mechanisms. In persons with complete spinal cord injuries above T-6, thermoregulation is substantially impaired because of the interruption of neuronal pathways to and from the hypothalamus. These same pathways are important in the production of fever in response to infections, and injury to these pathways in patients with high-level spinal cord injuries should diminish their ability to mount a febrile response. In clinical practice, however, measurements of body temperature are used to make decisions in patients with spinal cord injuries in a manner similar to that in patients without spinal cord injuries. In this article, we review the literature on thermoregulation and fever in normal persons and in those with complete spinal cord injuries and propose possible mechanisms for fever in persons with high-level spinal cord injuries
      Autonomic dysfunction is a frequent complication in patients with complete upper thoracic and cervical spinal cord injuries. This disorder often results in impaired thermoregulation. Thus, persons with high-level spinal cord injuries are cautioned to avoid exposure to environmental temperature extremes because of their impaired ability to maintain a normal core body temperature. Both hypothermia and hyperthermia are potentially fatal complications of exposure to environmental extremes.
      The hypothalamus, often referred to as the body's thermostat, is responsible for integrating information from temperature sensors and for maintaining temperature homeostasis through its control of thermoregulatory functions. This ability is severely impaired after interruption of the efferent pathways of the hypothalamus in patients with complete high-level spinal cord injuries.
      Fever is also thought to be regulated by the hypothalamus and its efferent pathways. Pyrogens initiate a series of reactions that cause the hypothalamus to increase its set-point temperature. Thermoregulatory processes initiated through spinal pathways increase the body temperature as if the body were exposed to cold environmental temperatures. Therefore, a high-level complete spinal cord injury should theoretically preclude a normal febrile response. In clinical practice, we use the measurements of body temperature to determine the probability of infections in patients with spinal cord injuries just as in patients without spinal cord injuries. In our experience, patients with quadriplegia respond to infections with fevers of a magnitude similar to those in patients without spinal cord injuries. Our observations, however, have not been verified, and little is known about the mechanisms of production of fever in patients with high-level spinal cord injuries.
      This review examines the literature on thermoregulation and fever. Several possible mechanisms of febrile responses in patients with high-level complete spinal cord injuries are proposed that could explain fevers of a magnitude similar to those experienced by patients without spinal cord injuries.

      MEASUREMENT OF BODY TEMPERATURE

      An understanding of the methods used in the measurement of body temperature is important in the interpretation of studies on thermoregulation. The ideal measurement of body temperature represents the general thermal status of the body tissues, especially the deep brain structures where the centers of temperature regulation are located. This measurement is often referred to as the “core” temperature.
      The single best representative measurement of body temperature is the temperature of mixed venous blood in the right atrium, which is virtually identical to arterial blood temperature.
      • Mitchell D
      • Laburn HP
      Pathophysiology of temperature regulation.
      In monkeys, arterial blood temperature has been shown to be similar to the temperatures in deep brain structures.
      • Hayward JN
      • Baker MA
      Role of cerebral arterial blood in the regulation of brain temperature in the monkey.
      Core body temperatures can also be accurately estimated with the measurement of esophageal temperature at the level of the heart.
      • Gass GC
      • Camp EM
      • Nadel ER
      • Gwinn TH
      • Engel P
      Rectal and rectal vs. esophageal temperatures in paraplegic men during prolonged exercise.
      • Strydom NB
      • Wyndham CH
      • Williams CG
      • Morrison JF
      • Bredell GAG
      • Joffe A
      Oral/rectal temperature differences during work and heat stress.
      • Cranston WI
      • Gerbrandy J
      • Snell ES
      Oral, rectal and oesophageal temperatures and some factors affecting them in man.
      • Cooper KE
      • Kenyon JR
      A comparison of temperatures measured in the rectum, oesophagus, and on the surface of the aorta during hypothermia in man.
      • Wyss CR
      • Brengelmann GL
      • Johnson JM
      • Rowell LB
      • Niederberger M
      Control of skin blood flow, sweating, and heart rate: role of skin vs. core temperature.
      • Brengelmann GL
      • Johnson JM
      • Hong PA
      Electrocardiographic verification of esophageal temperature probe position.
      The obvious difficulties with these measurements, however, preclude their use in routine clinical practice. Measurements of esophageal temperature have been used in clinical investigations in conscious subjects although anesthetized or comatose subjects tolerate such measurements much better.
      Rectal temperatures are often considered the most accurate core temperature measurement used in clinical practice.
      • Mitchell D
      • Laburn HP
      Pathophysiology of temperature regulation.
      • Strydom NB
      • Wyndham CH
      • Williams CG
      • Morrison JF
      • Bredell GAG
      • Joffe A
      Oral/rectal temperature differences during work and heat stress.
      Usually, they reflect the temperature of the blood in the steady state, although they are slightly higher than arterial blood temperatures.
      • Cranston WI
      • Gerbrandy J
      • Snell ES
      Oral, rectal and oesophageal temperatures and some factors affecting them in man.
      In certain circumstances, however, rectal temperatures do not accurately reflect the core body temperature. Rectal temperatures depend on the depth of penetration by the thermistor
      • Sawka MN
      • Latzka WA
      • Pandolf KB
      Temperature regulation during upper body exercise: able-bodied and spinal cord injured.
      and are influenced by the local rate of blood flow.
      • Grayson J
      Observations on the temperature of the human rectum.
      Studies have shown that rectal temperatures lag behind central (deep brain) temperature changes in the non-steady-state condition and therefore poorly reflect changes occurring at the thermoregulation centers.
      • Cranston WI
      • Gerbrandy J
      • Snell ES
      Oral, rectal and oesophageal temperatures and some factors affecting them in man.
      • Downey JA
      • Darling RC
      • Chiodi HP
      The response of tetraplegic patients to cold.
      Temperatures at the tympanic membrane are occasionally used in clinical practice and in studies on thermoregulation. Changes in temperature near the tympanic membrane are thought to correlate closely with those at the central temperature receptors.
      • Downey JA
      • Darling RC
      • Chiodi HP
      The response of tetraplegic patients to cold.
      • Cooper KE
      • Cranston WI
      • Snell ES
      Temperature in the external auditory meatus as an index of central temperature changes.
      • Tarn H-S
      • Darling RC
      • Cheh H-Y
      • Downey JA
      The dead zone of thermoregulation in normal and paraplegic man.
      The absolute temperature at the tympanic membrane is lower than the temperature of the blood, however, and may vary with the ambient temperature and the proximity of the thermistor to the tympanic membrane.
      • Cooper KE
      • Cranston WI
      • Snell ES
      Temperature in the external auditory meatus as an index of central temperature changes.
      Changes in oral sublingual temperatures are also thought to correlate closely with central temperature changes although the absolute values are lower than those in blood temperatures.
      • Cranston WI
      • Gerbrandy J
      • Snell ES
      Oral, rectal and oesophageal temperatures and some factors affecting them in man.
      • Tarn H-S
      • Darling RC
      • Cheh H-Y
      • Downey JA
      The dead zone of thermoregulation in normal and paraplegic man.
      They are influenced by breathing through the mouth and are technically difficult to monitor for long periods during thermoregulation studies. Study subjects must keep the thermistor in a sublingual position without opening their mouth; this method essentially excludes use in subjects who are exercising. Oral supralingual temperatures are less accurate than sublingual temperatures because they are affected by the ambient temperature.
      Bladder and vaginal temperatures are similar to rectal temperatures. They represent the core body temperature in the steady state but may have a prolonged lag time during dynamic changes in temperature and are rarely used in thermoregulatory investigations. Axillary and other skin temperatures are mainly useful for studying the state of vasomotor tone in the periphery and correlate poorly with core body temperature.
      The precautions in interpreting temperature measurements in patients with spinal cord injuries are the same as those in persons without spinal cord injuries. An additional consideration in patients with spinal cord injuries is that the peripheral hemodynamics may differ from those in patients without spinal cord injuries. Rectal, bladder, and vaginal temperatures may underestimate the body temperature because of the relative nominal venous return from the paralyzed lower extremities. The error is probably minimal in resting subjects but may be of more concern in investigations of the thermal strain on patients with paraplegia during exercise of the upper extremities.
      • Gass GC
      • Camp EM
      • Nadel ER
      • Gwinn TH
      • Engel P
      Rectal and rectal vs. esophageal temperatures in paraplegic men during prolonged exercise.

      THERMOREGULATION IN NORMAL PERSONS

      Thermoregulation is the ability to maintain homeostasis in body temperature by balancing heat production and heat loss. Heat is produced through metabolic processes and lost through conduction, radiation, and evaporation.
      • Guyton AC
      The human body has a remarkable ability to maintain a constant core temperature despite wide variations in ambient temperatures. A normal unclothed adult can regulate core temperature within 0.6°C indefinitely between ambient temperatures of 13°C and 60°C in dry air. Thermoregulatory mechanisms are generally activated at ambient temperatures that are less than 27°C and greater than 33°C, and the “thermoneutral zone” is between 27°C and 33°C.
      • Mitchell D
      • Laburn HP
      Pathophysiology of temperature regulation.
      No single body temperature can be considered normal. The average normal oral temperature is 37°C, and the normal range under resting conditions is from 36°C to 37.3°C. The human body is not 100% efficient at thermoregulation, and several factors, such as environmental temperature, emotional state, phase of the menstrual cycle in women, and exercise, can cause body temperatures to deviate from normal.
      • Mitchell D
      • Laburn HP
      Pathophysiology of temperature regulation.
      • Guyton AC
      Strenuous exercise may increase body temperature for several hours. Rugby players have been shown to have rectal temperatures that exceed 39°C after a game,
      • Cohen I
      • Mitchell D
      • Seider R
      • Kahn A
      • Phillips F
      The effect of water deficit on body temperature during rugby.
      and marathon runners have had rectal temperatures as high as 43°C.
      • Sutton JR
      43°C in fun runners!.
      In addition, each individual has a unique consistent circadian rhythm that is difficult to disturb. In a study conducted by the National Institutes of Health, the oral temperatures of normal volunteers peaked at approximately 6 p.m. each day, and the amplitude was generally less than 0.5°C.
      • Dinarello CA
      • Wolff SM
      Pathogenesis of fever in man.
      The thermoregulatory thermostat is located in the hypothalamus. The function of the hypothalamus is to integrate information from temperature sensors and to modify body temperatures appropriately through its efferent control of thermoregulatory processes. It also attempts to maintain body temperature at a constant set-point.
      The heat-sensitive temperature sensors are primarily located in the preoptic region in the anterior hypothalamus. The skin also has warmth receptors but relatively few in comparison with the numerous cold receptors. Additional cold-sensitive receptors are probably located in the hypothalamus, midbrain, spinal cord, and other internal structures. The afferent connections of all the cold sensors probably lead to the hypothalamus.
      The hypothalamus integrates the information on body temperature that it receives from all the temperature sensors in the body. If it determines that the body temperature is too warm, heat-decreasing mechanisms will be initiated. Then sympathetic centers in the hypothalamus will be inhibited; this outcome results in generalized dilatation of the blood vessels of the skin. This process may increase the rate of transfer of heat by eightfold. The decrease in total body sympathetic stimulation and the resultant decline in circulating catecholamines will also decrease the cellular metabolism and the production of heat.
      The hypothalamus is also responsible for the initiation of sweating, which is potentially the most powerful autonomic mechanism to decrease body heat. Sweating can dissipate heat from the body at a rate more than 10 times the resting metabolic production of heat.
      • Guyton AC
      The heat-sensitive neurons in the hypothalamus also communicate to the cerebral cortex that the body temperature is above normal. This signal will generally result in the volitional behavior of seeking a cool environment.
      The opposite thermostatic mechanisms will be instituted if the body temperature is cooler than the hypothalamic set-point temperature. The sympathetic centers in the hypothalamus will be excited; this situation results in peripheral vasoconstriction for conservation of heat. The generalized increase in sympathetic stimulation will also increase the rate of cellular metabolism (chemical thermogenesis) directly as well as through its stimulation of the adrenal glands to release catecholamines. In adults, however, chemical thermogenesis can increase the rate of production of heat by no more than 10 to 15%.
      • Guyton AC
      Shivering is the most potent method that the body has to increase metabolism and production of heat. During maximal shivering, total production of body heat can increase as much as 4 to 5 times above the normal resting metabolism. Cold signals from skin receptors and other sites stimulate the primary center for shivering, which is located in the posterior hypothalamus. Its efferent connections are with anterior motor neurons in the spinal cord for the stimulation of shivering. Piloerection is also stimulated, but its importance in conservation of heat in humans is minimal.
      • Guyton AC
      Cellular metabolism can also be enhanced by the increased production of thyroxine by the thyroid gland, which is regulated by the hypothalamus; however, several weeks are necessary for the thyroid to hypertrophy and increase the production of thyroxine. Cellular metabolism may be increased severalfold in the acclimatized body after exposure to prolonged cold.
      The cortex of the brain is also involved with conservation of heat. The sensation of being too cold results in heat-seeking behavior to reestablish comfort.
      The role of the hypothalamus as the primary thermoregulatory center is well established; however, some thermoregulatory processes, such as local or spinal cord reflexes, can be at least partially controlled at levels other than the hypothalamus. These mechanisms have not been unequivocally elucidated and are a subject of controversy in the literature.
      Thermoregulatory vasomotor activity depends on dual control from the hypothalamus and from the local reflexes. Heating or cooling one region of the body will result in appropriate changes in local and regional vasomotor tone independent of the core body temperature. Kerslake and Cooper
      • Kerslake DM
      • Cooper KE
      Vasodilatation in the hand in response to heating the skin elsewhere.
      demonstrated vasodilatation of the hand concomitant with a decrease in central temperature during radiant heating of the trunk. These local vasomotor reflexes are able to override the messages sent from the hypothalamus, although extremes in local temperature may be necessary.
      • Bryce-Smith R
      • Coles DR
      • Cooper KE
      • Cranston WI
      • Goodale F
      The effects of intravenous pyrogen upon the radiant heat induced vasodilatation in man.
      Sweating and shivering are influenced by local changes in temperature; however, their primary control is from the hypothalamus. Local heating of the skin can initiate sweating, and local cooling of the skin can initiate shivering. The precise mechanisms, although undetermined, are thought to be through local end-organ or spinal cord reflexes. The temperature of the skin interacts with the hypothalamic temperature in the regulation of the intensity of these thermoregulatory responses and their temperature thresholds. Sweating begins at a low hypothalamic temperature and is more intense the warmer the temperature of the skin. Conversely, shivering begins at a high hypothalamic temperature and is more intense the cooler the temperature of the skin.
      The primary thermoregulatory mechanisms under resting conditions in neutral ambient temperatures do not rely on sweating or shivering. Downey and associates
      • Tarn H-S
      • Darling RC
      • Cheh H-Y
      • Downey JA
      The dead zone of thermoregulation in normal and paraplegic man.
      • Downey JA
      • Huckaba CE
      • Myers SJ
      • Darling RC
      Thermoregulation in the spinal man.
      refer to the core body temperature between the hypothalamic set-point and the thresholds for sweating and shivering as the “dead band.” The vasomotor system and behavior are primarily responsible for thermoregulation within this zone.

      THERMOREGULATION IN PERSONS WITH SPINAL CORD INJURIES

      The disruption of the spinal pathways in persons with spinal cord injuries decreases their ability to regulate body temperature. Subjects with complete spinal cord injuries above the T-6 level usually have difficulty maintaining a normal core temperature in relationship to changes in environmental temperature and are referred to as being “partially poikilothermic.” Consequently, persons with high-level spinal cord injuries are advised to avoid extremes in ambient temperature because they are susceptible to both hypothermia and hyperthermia.
      • Bloch RF
      Autonomic dysfunction.
      • Altus P
      • Hickman JW
      • Nord HJ
      Accidental hypothermia in a healthy quadriplegic patient.
      • Menard MR
      • Hahn G
      Acute and chronic hypothermia in a man with spinal cord injury: environmental and pharmacologic causes.
      A complete cervical spinal cord injury has the most profound effect on thermoregulation. A loss of afferent pathways from peripheral cold sensors below the level of the injury occurs as well as a loss of hypothalamic thermoregulatory control to most of the body. Shivering can occur only above the level of the spinal cord injury, and thermoregulatory sympathetically mediated changes in vasomotor tone, metabolism, and sweating will theoretically be absent from the entire body (sympathetic outflow occurs from T-1 to L-2). Therefore, after a cervical spinal cord injury, thermoregulation depends on behavioral modification of the environment, local vasomotor reflexes, basal metabolic rate, and shivering above the level of the injury (Table 1). Behavioral modification may be the most important thermoregulatory mechanism in persons with high-level spinal cord injuries. Additional thermoregulatory mechanisms, such as the increased use of “panting” to increase heat loss, have been suggested
      • Johnson RH
      Temperature regulation in paraplegia.
      but have not been verified. The role of other thermoregulatory reflexes independent of the hypothalamus (that is, spinal reflex sweating) is controversial.
      Table 1Mechanisms That Affect Thermoregulation in Normal Persons and Those With Spinal Cord Injuries
      * CT = chemical thermogenesis; LOI = level of injury.
      Thermoregulatory reflexes
      MechanismsNormal personsPersons with quadriplegiaPersons with paraplegia
      To increase body temperature
       VasoconstrictionFirst-line mechanismLocal reflexes onlyAbove LOI + local reflexes
       Environmental modificationFirst-line mechanismHeat-seeking behaviorHeat-seeking behavior
       ShiveringMost potentAbove LOIAbove LOI
       MetabolismLess potentShivering above LOI + thyroid activity increases (weeks)Shivering above LOI + thyroid activity increases (weeks) + CT increases (sympathetic center)
      CT increases (immediately) + thyroid activity increases (weeks)
      To decrease body temperature
       VasodilatationFirst-line mechanismLocal reflexes onlyAbove LOI + local reflexes
       Environmental modificationFirst-line mechanismCold-seeking behaviorCold-seeking behavior
       SweatingMost potentLocal or spinal reflexes (?)Above LOI + reflexes below LOI (?)
       MetabolismLess potentThyroid activity decreases (weeks)Thyroid activity decreases (weeks) + CT decreases (sympathetic center)
      CT decreases (immediately) + thyroid activity decreases (weeks)
      * CT = chemical thermogenesis; LOI = level of injury.
      Wallin and Stjernberg
      • Wallin BG
      • Stjernberg L
      Sympathetic activity in man after spinal cord injury: outflow to skin below the lesion.
      provided evidence that no thermoregulatory spinal reflexes are present after a complete spinal cord injury. Microelectrode recordings of the peroneal nerve in subjects with spinal cord injuries showed no change in neuronal activity after alterations in ambient temperature. Some investigators, however, have confirmed sweating in persons with quadriplegia and below the level of injury in persons with paraplegia in response to increased ambient temperatures.
      • Randall WC
      • Wurster RD
      • Lewin RJ
      Responses of patients with high spinal transection to high ambient temperatures.
      • Seckendorf R
      • Randall WC
      Thermal reflex sweating in normal and paraplegic man.
      • Huckaba CE
      • Frewin DB
      • Downey JA
      • Tam HS
      • Darling RC
      • Cheh HY
      Sweating responses of normal, paraplegic and anhidrotic subjects.
      Seckendorf and Randall
      • Seckendorf R
      • Randall WC
      Thermal reflex sweating in normal and paraplegic man.
      concluded that spinal cord thermoregulatory reflex sweating “appears a certainty” because all central neuronal connections had been disrupted. They noted, however, that the intensity of sweating was diminished in the entire body in subjects with quadriplegia and below the level of injury in subjects with paraplegia; these findings suggest that higher central nervous facilitation is essential for normal sweating intensity. These investigators did not consider that sweating in their subjects may have been through local end-organ reflexes. Other investigators have been unable to verify thermoregulatory sweating in conjunction with central or environmental heating in persons with quadriplegia or below the level of injury in persons with paraplegia.
      • Johnson RH
      Temperature regulation in paraplegia.
      • Downey JA
      • Huckaba CE
      • Kelley PS
      • Tam HS
      • Darling RC
      • Cheh HY
      Sweating responses to central and peripheral heating in spinal man.
      • Boshes B
      • Blustein H
      Survival of sympathetic nervous system after spinal cord injury as measured by sweat mechanism.
      • Guttmann L
      • Silver J
      • Wyndham CH
      Thermoregulation in spinal man.
      Sweating, however, will occur as a nonthermoregulatory reflex in persons with high-level spinal cord injuries and autonomic hyperreflexia.
      Shivering may occur as a thermoregulatory spinal or local end-organ reflex; however, supraspinal facilitation is necessary, and shivering does not occur below the level of the spinal cord injury. Much of the available knowledge of the physiologic aspects of shivering in thermoregulation is from studies of subjects with spinal cord injuries. Downey and colleagues
      • Downey JA
      • Darling RC
      • Chiodi HP
      The response of tetraplegic patients to cold.
      • Downey JA
      • Huckaba CE
      • Myers SJ
      • Darling RC
      Thermoregulation in the spinal man.
      • Downey JA
      • Chiodi HP
      • Darling RC
      Central temperature regulation in the spinal man.
      • Downey JA
      • Miller JM
      • Darling RC
      Thermoregulatory responses to deep and superficial cooling in spinal man.
      confirmed the importance of previously proposed
      • Johnson RH
      • Spalding JMK
      The role of a central temperature receptor in shivering in man.
      • Sherrington CS
      Notes on temperature after spinal transection, with some observations on shivering.
      central cold temperature sensors (most cold sensors are thought to be in the skin). They showed that subjects with spinal cord injuries shivered in their innervated muscles when the central temperature (tympanic membrane temperature) was decreased to approximately 35.6°C, whereas the sentient skin was warm. Subjects with mid-thoracic or low-thoracic paraplegia, however, started shivering at higher temperatures than did those with quadriplegia when the sentient skin was exposed to cool temperatures; this finding suggests an interrelationship between central and peripheral cold receptors in the threshold for shivering. Downey and co-workers
      • Downey JA
      • Chiodi HP
      • Darling RC
      Central temperature regulation in the spinal man.
      • Downey JA
      • Miller JM
      • Darling RC
      Thermoregulatory responses to deep and superficial cooling in spinal man.
      also demonstrated the importance of cellular metabolism and production of heat in thermoregulation. In cold temperatures, subjects with quadriplegia could increase their metabolism (which is measured by consumption of oxygen) up to 100%, and those with mid-thoracic or low-thoracic paraplegia could increase their metabolism by 200%. They suggested that subjects with paraplegia could increase their metabolism more because of the greater mass of innervated muscle available for shivering.
      Changes in thermoregulatory vasomotor tone are thought to occur through spinal cord reflexes only if supraspinal facilitation exists. Although radiant heat applied to the trunk will reflexively cause vasodilatation in the hand in a normal subject even with a decreasing central temperature,
      • Kerslake DM
      • Cooper KE
      Vasodilatation in the hand in response to heating the skin elsewhere.
      it will cause no change in vasomotor tone in the hand of a subject with a complete cervical spinal cord injury.
      • Johnson RH
      • Spalding JMK
      The effect of surface and central temperature on hand blood flow in subjects with complete transection of the cervical cord.
      Local end-organ vasomotor reflexes, however, do occur in subjects with high-level spinal cord injuries. Randall and associates
      • Randall WC
      • Wurster RD
      • Lewin RJ
      Responses of patients with high spinal transection to high ambient temperatures.
      showed that vasodilatation in response to increased ambient temperatures occurs in the lower extremities of persons with complete cervical spinal cord injuries in whom neuronal connections with the hypothalamus have been disrupted.
      Foerster
      • Foerster O
      Die Störungen der Thermoregulation.
      proposed that the spinal cord can act as a thermoregulatory thermostat similar to the hypothalamus. This concept was supported by the experiments of Simon,
      • Simon E
      Temperature regulation: the spinal cord as a site of extrahypothalamic thermoregulatory functions.
      who was able to induce shivering in dogs by selectively cooling the spinal cord. The difficulty of thermoregulation in persons with high-level spinal cord injuries, however, opposes the suggestion that the spinal cord has thermoregulatory capabilities independent of the hypothalamus in humans.
      The loss of afferent information from peripheral temperature sensors may alter the hypothalamic threshold temperatures for shivering and sweating. Tarn and colleagues
      • Tarn H-S
      • Darling RC
      • Cheh H-Y
      • Downey JA
      The dead zone of thermoregulation in normal and paraplegic man.
      demonstrated that the core threshold temperature for sweating was increased 0.7°C in subjects with paraplegia. Attia and Engel
      • Attia M
      • Engel P
      Thermoregulatory set point in patients with spinal cord injuries (spinal man).
      found that subjects with spinal cord injuries had a wider thermoneutral zone and proposed that such subjects can change their thermoregulatory set-point on the basis of the ambient temperature.
      Autonomic dysfunction as manifested in orthostatic hypotension after a spinal cord injury generally diminishes with time;
      • Menard MR
      • Hahn G
      Acute and chronic hypothermia in a man with spinal cord injury: environmental and pharmacologic causes.
      • Mathias CJ
      • Frankel HL
      Clinical manifestations of malfunctioning sympathetic mechanisms in tetraplegia.
      however, the ability of subjects with high-level spinal cord injuries to improve their thermoregulatory capabilities with time has not been demonstrated. In contrast, Claus-Walker and co-workers
      • Claus-Walker J
      • Halstead LS
      • Carter RE
      • Campos RJ
      • Spencer WA
      • Canzoneri III, J
      Physiological responses to cold stress in healthy subjects and in subjects with cervical cord injuries.
      found that the ability of subjects with quadriplegia to adapt to cold decreased with time.

      FEVER IN NORMAL PERSONS

      Fever is the result of normal thermoregulatory processes attempting to increase the body temperature above normal. The hypothalamic thermostat functions as if its set-point temperature is reset at a higher level. This outcome results in peripheral vasoconstriction and heat-seeking behavior to conserve heat and an increase in sympathetically mediated body metabolism to increase production of heat. Shivering (shaking chills) may also occur in order to increase the production of heat.
      Fever may occur with infections, malignant involvement, immunologic diseases, and noninfective inflammatory diseases. The pathophysiologic features of fever are thought to be similar whatever the cause. The cascade that ultimately results in fever is initiated by the effects of agents (for example, infectious organisms, antibody-antigen reactions, and tumor cells) on blood monocytes and tissue macrophages. These cells are stimulated to produce interleukin 1, often referred to as “endogenous pyrogen.” Interleukin 1 is a hormone that has numerous biologic activities, including several that are important for host defense. The synthesis of interleukin 1 necessitates RNA transcription, and it cannot be detected in the bloodstream for several hours after its production is stimulated. After interleukin 1 is released, it travels to the brain, where it acts through intermediaries on the hypothalamus to increase its set-point temperature. One such intermediary is thought to be a prostaglandin of the E series. The experimental injection of prostaglandin E into the hypothalamus increases the body temperature. This factor explains the decrease in fever produced by the classic antipyretic agents (aspirin and nonsteroidal anti-inflammatory drugs) that block the production of prostaglandins. Other unknown intermediaries may be involved with increasing the hypothalamic set-point. The result is the stimulation of normal thermoregulatory mechanisms to increase body temperature (as previously described).
      • Mitchell D
      • Laburn HP
      Pathophysiology of temperature regulation.
      • Dinarello CA
      • Wolff SM
      Pathogenesis of fever in man.
      • Atkins E
      Fever: the old and the new.
      Fever can be produced experimentally in humans by injecting bacterial endotoxin into the bloodstream. Buskirk and colleagues
      • Buskirk ER
      • Thompson RH
      • Rubenstein M
      • Wolff SM
      Heat exchange in men and women following intravenous injection of endotoxin.
      demonstrated that after bacterial endotoxin was injected, the metabolism was increased and the blood flow was redistributed away from the skin; these changes decreased the skin and subcutaneous temperatures. The changes in blood flow were typically noted in slightly less than 1 hour, and the increase in metabolism was detected in 1 to 3 hours. Core temperature measurements (esophageal, rectal, and tympanic membrane) increased above normal in 2 to 4 hours after injection of bacterial endotoxin and usually followed the vasomotor and metabolic changes. Other investigators have demonstrated a slightly faster pyrogenic response after injection of bacterial endotoxin; however, the type and dosage of endotoxins varied.
      • Bryce-Smith R
      • Coles DR
      • Cooper KE
      • Cranston WI
      • Goodale F
      The effects of intravenous pyrogen upon the radiant heat induced vasodilatation in man.
      • Gerbrandy J
      • Cranston WI
      • Snell ES
      The initial process in the action ofbacterial pyrogens in man.

      FEVER IN PERSONS WITH QUADRIPLEGIA

      The ability of the body to thermoregulate is seriously disturbed in persons with complete quadriplegia. Theoretically, this impairment should profoundly affect the ability of the body to mount a febrile response. Endogenous pyrogens are able to increase the hypothalamic set-point, but the hypothalamus is unable to respond with sympathetically controlled vasoconstriction and increased cellular metabolism. The only thermoregulatory mechanisms the hypothalamus has to increase body temperature are shivering above the level of the injury and stimulation of warmth-seeking behavior.
      A review of the literature provides minimal evidence, except for rare case reports,
      • Ohry A
      • Heim M
      • Rozin R
      Peculiar septic responses in traumatic tetraplegic patients.
      that subjects with complete cervical spinal cord injuries are unable to mount fevers in response to infections. In hospitalized patients with spinal cord injuries, febrile responses to infections have been noted,
      • Sugarman B
      • Brown D
      • Musher D
      Fever and infection in spinal cord injury patients.
      and our own clinical impression is that patients with complete quadriplegia have fevers of a magnitude similar to that in patients without spinal cord injuries. Several untested theories, including the following, could explain fevers in our patients with quadriplegia.
      • 1.
        The remaining thermoregulatory mechanisms controlled by the hypothalamus are sufficient to cause fever. This concept seems unlikely because the only remaining mechanisms that increase body temperature are warmth-seeking behavior and shivering above the level of the injury.
      • 2.
        Hypothalamic thermoregulation occurs by mechanisms other than efferent neurologic pathways. For example, humoral factors may be released that cause peripheral vasoconstriction or increase cellular metabolism.
      • 3.
        Pyrogens or their stimulated products (endogenous pyrogens) may affect anatomic sites other than the hypothalamus. For example, they may act directly on blood vessels to cause vasoconstriction or on cells to increase metabolism.
      • 4.
        Knowledge of the mechanism of how the body increases temperature in fever is incomplete.
      • 5.
        Autonomic spinal cord tracts are resistant to injury and often remain intact despite complete motor and sensory interruption.

      CONCLUSION

      Thermoregulation is controlled primarily by the hypothalamus, which integrates information on body temperature from peripheral and central temperature sensors and regulates body temperature through its effector mechanisms. The center for shivering is located in the hypothalamus, as are the sympathetic centers that control sweating, changes in metabolism, and changes in vasomotor tone. Fever occurs when the hypothalamus increases its set-point temperature and uses the thermoregulatory mechanisms under its control to increase body temperature.
      Persons with complete high-level spinal cord injuries have lost much of their ability to thermoregulate; this factor results in partial poikilothermia. Sympathetic control to the entire body is disrupted in a person with a complete cervical spinal cord injury, as is the ability to shiver below the level of the injury. Local vasomotor reflexes and, possibly, spinal reflex sweating have a role in thermoregulation, but behavioral control of environmental temperature may be the most important method of thermoregulation. Theoretically, the ability to mount a febrile response should be profoundly diminished in persons with quadriplegia; however, the information that suggests that such subjects do not have fevers of normal magnitude in response to infections is minimal. Further studies are needed to verify that infected patients with high-level complete spinal cord injuries have fevers of normal magnitude and to elucidate which mechanisms are important in the production of fever in this population.

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