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Multiple Triggers for Hyperthermic Fatigue and Exhaustion

Cheung, Stephen S.1; Sleivert, Gordon G.2

Exercise and Sport Sciences Reviews: July 2004 - Volume 32 - Issue 3 - p 100-106
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CHEUNG, S. S., and G. G. SLEIVERT. Multiple triggers for hyperthermic fatigue and exhaustion. Exerc. Sport Sci. Rev., Vol. 32, No. 3, pp. 100–106, 2004. It has been proposed that a critical body temperature exists at which muscle activation is impaired through a direct effect of high brain temperature decreasing the central drive to exercise, but other factors may also inhibit performance in the heat. An integrative physiological model is presented to stimulate research into mechanisms of hyperthermic fatigue and exhaustion.

Elevated internal body temperatures may directly limit exercise tolerance because of alterations in brain function and local tissue blood flow.

1Environmental Ergonomics Laboratory, School of Health & Human Performance, Dalhousie University, Halifax, Nova Scotia, Canada, and 2Human Performance Laboratory, Faculty of Kinesiology, University of New Brunswick, Fredericton, New Brunswick, Canada

Address for correspondence: Dr. Stephen S. Cheung, Associate Professor, School of Health and Human Performance, Dalhousie University, 6230 South Street, Halifax, Nova Scotia, Canada B3H-3J5 (E-mail: stephen.cheung@dal.ca).

Accepted for publication: March 11, 2004.

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INTRODUCTION

Hyperthermia increases the physiological strain on the body and can result in a marked decrease in exercise capacity, potentially building to exhaustion, heat injury, and death. An evolutionary perspective suggests that physiological safeguards should protect individuals before catastrophic hyperthermia. Various animals will cease exercise when their core temperatures exceed safe limits, and some research suggests there may be a similar behavioral response in humans to reduce metabolic heat production and ultimately to protect physiological integrity.

Thus, the hypothesis that a critically high internal body temperature directly accelerates fatigue and may precipitate exhaustion has been an emerging theme in the literature, but the underlying mechanisms are not well understood. There are at least two major sets of homeostatic disturbances that could contribute to impaired ability to exercise during hyperthermia. First, there is some evidence that thermal strain—an elevation of body and specifically brain temperature—directly may elicit fatigue by impairing central arousal or the voluntary activation of muscle. Second, thermal strain usually is accompanied by high levels of cardiovascular strain, and an impairment of blood pressure or critical levels of blood flow to the brain and the splanchnic tissues may accelerate fatigue and may precipitate exhaustion. This review places the recent research into these two mechanisms within the overall context of the critical internal temperature hypothesis in the hopes of stimulating further research into the relationship between body temperature and fatigue during exercise in the heat.

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CRITICAL INTERNAL TEMPERATURE HYPOTHESIS

Interest in the direct effects of elevated temperatures per se as a mechanism for eliciting fatigue stems from studies reporting that subjects exercising in the heat seemed to reach the point of voluntary fatigue at similar and consistent core body temperatures despite various experimental manipulations (Table 1). Fuller et al. (4) exposed rats to different ambient temperatures before exercise and altered heat storage during exercise and reported consistent hypothalamic temperatures of 40.1–40.2°C at the point of voluntary fatigue. Similarly, Gonzalez-Alonso et al. (5) reported consistent final core and thigh temperature (40.1–40.3°C and 40.7–40.9°C, respectively) at voluntary exhaustion in 40°C heat in trained humans, despite differences in starting core temperature, rate of heat storage, and final skin temperature.

TABLE 1

TABLE 1

The same consistency of core temperature at voluntary fatigue during exercise-induced hyperthermia has been observed across fitness groups. Cheung and McLellan (1) reported that moderately fit individuals reached the point of voluntary exhaustion at a consistent rectal temperature (Tre) of approximately 38.7°C in an uncompensable heat stress environment regardless of hydration and acclimation status. This consistency in endpoint Tre suggests that moderately fit individuals are indeed capable of exercising to voluntary physiological exhaustion and that exercise heat tolerance with uncompensable heat stress similarly may be limited by a critical internal temperature. However, one clear benefit of aerobic fitness is the ability to tolerate a higher Tre at the point of voluntary fatigue, with highly fit individuals having a lower initial Tre (≈0.2°C) coupled with a higher final Tre of approximately 0.7°C (1).

To investigate further the effects of fitness on exercise heat tolerance, Selkirk and McLellan (14) isolated the separate effects of aerobic fitness and adiposity by systematically selecting four groups of males based on aerobic fitness and adiposity: (1) trained and low adiposity, (2) trained and high adiposity, (3) untrained and low adiposity, and (4) untrained and high adiposity. Voluntary tolerance to uncompensable heat stress was significantly longer in trained and low adiposity group than in any other group, with the main determinant being the ability of trained and low adiposity persons to tolerate a higher final core temperature; this difference was as much as 0.9°C compared with untrained and low adiposity persons. Overall, the consistent difference in thermal endpoint across fitness groups reported by these studies suggests that the capacity for heat storage may be a determinant in heat tolerance and that the thermal set point for hyperthermic exhaustion is shifted upward with increasing fitness (Table 1). However, the cardiovascular strain for these studies was near maximal, and differences in the efficiency of blood flow distribution to the muscles, skin, brain, and gastrointestinal tract across fitness groups may have driven the onset of fatigue (13).

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BRAIN FUNCTION DURING HYPERTHERMIA

Changes in behavior accompanying overheating, such as confusion, loss of coordination, and syncope, and, in extreme hyperthermia, loss of consciousness or seizures, have been consistently observed, indirectly suggesting a change in central nervous system function with hyperthermia (Fig. 1). Only in animal studies have brain temperatures been reported during exercise. The hypothalamic temperatures of the rats at exhaustion with treadmill exercise (40.1–40.2°C) were similar across different pre-exercise core temperatures and exercise ambient temperatures (4). Additionally, run time to exhaustion was significantly reduced after the preheating protocol, suggesting that animals exhaust at a specific, elevated brain temperature during maximal exercise regardless of the duration (4).

Figure 1.

Figure 1.

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Brain Activity and Rate of Perceived Exertion (RPE)

Brain activity, specifically the ratio of low frequency (α = 8–13 Hz) and high frequency (β = 13–30 Hz) brain waves as an indicator of arousal during hyperthermia and exercise has been explored in subjects cycling at 60% aerobic power in both a hot (≈40°C) and cool (≈19°C) environment (8), with a reduction in β waves in the hot exercise condition such that the ratio of α to β waves was increased. This is similar to what happens during sleep, so it may reflect a reduced state of arousal in hyperthermic subjects. Furthermore, the magnitude of increase in the α-to-β wave ratio was strongly correlated to elevated core temperature (r2 = 0.94–0.98) (8). Similarly, with passive hyperthermia, a reduction in electroencephalographic frequency has been reported in primates, but not until a brain (epidural) temperature of approximately 41.5°C (3). The functional significance of altered electroencephalographic activity remains to be determined, but it is worth noting that the altered brain activity was associated with changes in ratings of perceived exertion (8). Subjects continually rated their effort higher during hyperthermic trials, with the best predictor of the RPE being a reduction in electroencephalographic frequency in the frontal cortex of the brain (8) (Fig. 2).

Figure 2.

Figure 2.

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Central Neuromuscular Drive

Hyperthermia may elicit voluntary fatigue through an impairment in neuromuscular functioning. With cycling-induced hyperthermia, a decrease in maximal voluntary contraction and interpolated twitch force was reported with both knee extension and grip strength, suggesting a decrease in central neuromuscular activation (11). This finding was supported by a decrease in voluntary activation and interpolated twitch force with passive hyperthermia (7). A reduction in the amount of central drive to the motor neuron pool during hyperthermia could be a result of two possibilities: either there is a reduction in the descending message from the higher brain impulses to the motor neurons, there is inhibition occurring at the site of the motor neurons subcortically, where afferent feedback may be decreasing the excitability of those motor neurons, or both. The latter has been referred to as the sensory feedback hypothesis and differs slightly from the central fatigue hypothesis in that sensory feedback from Type III and IV afferent fibers, or from other sources, inhibits motor neurons at the level of the spinal cord, not the brain. Of course, feedback from other sources, in particular, feedback from baroreceptors or metaboreceptors, key receptors in cardiovascular control, also may influence hyperthermic fatigue at the level of the brain.

Other factors also may influence hyperthermic fatigue, including the contractile properties of the active muscle mass. Isometric force production has been shown to decrease when muscle temperature is elevated to 38.6°C, and consequently, a warmer muscle fatigues earlier than a slightly cooler muscle at the same absolute force. This is because the muscle twitch responds at a faster rate in the heat, and consequently it takes an increase in firing rate of the motor neurons at the same relative frequency to produce enough summation to maintain a given contraction over longer durations. Half-relaxation time and time to peak twitch force for the knee extensors decreased with heating, and this may have precipitated the need for a higher motor-unit firing frequency to maintain maximal voluntary contraction (MVC) (7). Thus, during hyperthermia, the peripheral properties of a heated muscle indirectly may contribute to the reduction in MVC through imposing a need for higher central drive to maintain force production.

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Neurohumoral Factors

Disturbances in cerebral neurotransmitter levels, especially serotonergic activity, have long been implicated in central fatigue, but very little work has been reported examining whether hyperthermia alters serotonin (5-hydroxytryptamine [5-HT]) levels in the brain. This neurotransmitter is of particular interest because it influences arousal levels, and if 5-HT levels increase, that could contribute to increases in perceived effort and the reduction in work rate, the exhaustion often observed during hyperthermia, or both. Certainly animal work suggests that pharmaceutically altering 5-HT concentration in the rat brain, through using agonist or antagonist drugs, either impairs (5-HT agonist) or enhances (5-HT antagonist) endurance, and in humans, a 5-HT agonist also impairs endurance performance (2). However, this work did not directly examine the influence of hyperthermia on fatigue, so it is difficult to extend this research and to suggest a role for 5-HT in hyperthermic fatigue

Dopamine is another neurotransmitter that is a candidate for modulating hyperthermic fatigue, because it plays a role in the control and initiation of movement and may also reduce 5-HT production. Levels of dopamine also have been shown to increase during exercise, and precipitous falls in dopamine coincide with early fatigue (2). Nybo et al. (12) reported that dopamine levels were elevated in both arterial and jugular venous samples during hyperthermia, but these elevated levels most likely were derived from other tissues besides the brain, and in fact were not related to an increase in cerebral dopamine release or increased uptake of the dopamine precursor tyrosine. More mechanistic work, perhaps using dopamine agonists or antagonists, is required to understand the influence of dopamine on hyperthermic fatigue and exhaustion.

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CARDIOVASCULAR LIMITATIONS DURING HYPERTHERMIA

It is important to note that many of the key studies investigating aspects of fatigue, exhaustion, and hyperthermia used exercise as a means of increasing core temperature (active hyperthermia) before testing the influence of temperature on various measures of cardiovascular and neuro-muscular function (5,11). From a performance point of view, the cardiovascular strain accompanying hyperthermia is not a confounding factor, but could indeed be the main factor underlying fatigue. However, from a mechanistic perspective, the high cardiovascular strain also acts to confound the interpretation regarding the direct effects of temperature on neuromuscular fatigue. For example, Gonzalez-Alonso et al. (5) reported heart rate values of 98–99% of maximum (198 ± 4 bpm) at exhaustion during their cycling protocol, and other studies have used an experimental endpoint of more than 95% of heart rate during exercise in the heat (1,14). Together, the combination of changes in hydration, cardiovascular strain, and baroreceptor and metaboreceptor feedback in these studies could be such that the critical temperature at fatigue was coincidental with high cardiovascular strain, rather than directly eliciting fatigue. Another emerging idea is that the impact of competition between metabolic and thermoregulatory demands for blood flow also may accelerate the onset of fatigue through localized ischemia in specific tissues such as the brain or gastrointestinal tract.

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Cerebral Blood Flow and Metabolism

Hyperthermia results in a decrease in the cerebral blood flow velocity during prolonged submaximal exercise in humans (10), and marked decreases in brain blood flow during exercise and hyperthermia have been measured in animal models, with decreases being particularly large and reaching critically low levels in unfit animals (13) (Fig. 3). These marked decreases in cerebral blood flow seem to be modulated by cerebral vasoconstriction, triggered by hyperventilation and a reduction in arterial carbon dioxide tension (10). Decreases in cerebral blood flow, however, are not necessarily associated with decreases in cerebral metabolism. Nybo et al. (10) observed that cerebral blood flow was decreased by approximately 20% in hyperthermia, but that cerebral glucose use actually increased by 7%. Core heating of 1.5°C is associated with an approximately 23% increase in resting metabolic rate and with an increase in metabolic activity in such brain structures as the cerebellum as well as the hypothalamus, the thermoregulatory center of the brain (9), along with concomitant decreases in the activity of other specific sites within the brain during hyperthermia. However, the relationship between increased brain temperature, cerebral metabolism, and exercise performance remains unclear.

Figure 3.

Figure 3.

It is possible that the increased cerebral metabolism in select areas during hyperthermia stresses the critical carbohydrate supply necessary for maintaining cerebral function. In a primate model (pig-tailed monkeys), severe hypoglycemia was reported to accompany hyperthermia (3), and in humans, it has been shown that the cerebral oxygen to carbohydrate uptake ratio is reduced after hyperthermic but not normothermic exercise (12). Given the increase of metabolic rate and energy demand in select regions of the brain and the hypoglycemia that accompanies hyperthermia, glycogen depletion of the brain could play a role in precipitating fatigue during hyperthermia in certain circumstances.

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Gastrointestinal Blood Flow and Endotoxemia

During severe exercise-induced hyperthermia, blood flow is markedly reduced to the gastrointestinal tract (Fig. 4), and this may compromise the integrity of the intestinal walls (13). As a result, the leakage of lipopolysaccharides (endotoxins) into the circulation is a well-documented response to severe exercise-induced hyperthermia. This endotoxemia can trigger a cascade of detrimental physiological responses, including a cytokine-mediated rise in hypothalamic set point, which can induce a fever-like situation and can accelerate heat storage and heat stroke. Of greater relevance to hyperthermic fatigue is the fact that endotoxemia triggers cytokine release, and cytokines have been implicated as factors that influence fatigue at the level of the central nervous system in infections like Epstein-Barr virus or in diseases such as chronic fatigue syndrome (2). Thus, further research is required to explore whether endotoxemia influences the brain to increase the perception of effort, to impair voluntary activation of muscle, or both (Fig. 5).

Figure 4.

Figure 4.

Figure 5.

Figure 5.

Another interesting consequence of endotoxemia that has been reported only recently is an impairment of skeletal muscle intrinsic force-generating capacity, in the order of 20–40%, for skinned fibers (rats) treated in vitro with endotoxins (15). Although few data have been reported, there is some evidence that contractile proteins are damaged by the endotoxemia-induced production of free radical species (15). Therefore, it is possible that the decrease in maximal voluntary contractile force and central neuromuscular drive observed with both exercise-induced (11) and passive (7) hyperthermia may be potentiated by an endotoxemic impairment of local muscular activity, and these factors may combine to induce fatigue and exhaustion.

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ISOLATING THERMAL VERSUS CARDIOVASCULAR INFLUENCES

As evident above, hyperthermic fatigue may be multifactorial mechanistically, and the effects of heat stress on thermal and cardiovascular strain often are tightly interwoven, especially with the use of exercise protocols resulting in high cardiovascular strain. A recent study in our laboratory investigated the influence of hyperthermia on fatigue using a passive heating protocol to remove the confounding effects of exercise stimulus and to minimize the confounding effects of high cardiovascular strain, achieving endpoint rectal temperatures of 39.5°C at only 65% of heart rate reserve (7) (Fig. 6).

Figure 6.

Figure 6.

We observed that MVC and voluntary activation were impaired by hyperthermia, even when cardiovascular strain was only moderate (7). Further, it seems that body core temperature was the primary thermal input causing hyperthermia-induced fatigue, because when the skin was cooled rapidly (by ≈8°C) and core temperature was held stable at approximately 39.5°C, there was no recovery of MVC or voluntary activation. Additionally, force and voluntary activation levels returned to baseline values on core cooling, indicating the ability to activate the muscle and to produce force was not depressed as a result of fatigue accumulating over the protocol, but likely directly influenced by body core temperature. During passive heating, there also were dramatic increases in both thermal discomfort and sensation, followed by dramatic decreases toward baseline with the introduction of cooling. Even though skin cooling markedly reduced psychophysical strain, it had no immediate influence on voluntary activation or MVC; therefore, our data (7) suggest that subjective perceptions of thermal strain did not influence hyperthermia-induced fatigue. Thus, these data support the work carried out by Nybo and Nielsen (11), who found decreases in force production and voluntary activation in hyperthermic subjects, and expand on their findings by differentiating the influences of core and skin temperature on hyperthermic fatigue. Together, these studies suggest that a high temperature per se is the most likely candidate influencing hyperthermic fatigue and exhaustion and suggest a limited direct role for cardiovascular feedback.

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VOLUNTARY CONTROL AND PERCEPTION OF EFFORT

The physiological impact of hyperthermia may be circumvented by voluntary control of effort during heat stress. An alternative explanation to the direct effect of a high core temperature accelerating fatigue recently was proposed by Marino et al. (6). These researchers observed that relative to African runners, there was a reduction in running speed of larger white athletes the moment they were exposed to running in hot conditions in which they could not maintain heat balance as well as in cool conditions. Thus, they slowed their running speed long before they became hot, as predicted by the model of central fatigue resulting from the attainment of some limiting body temperature. These researchers proposed that it is not so much a fatigue process that limits exercise performance in the heat, but an anticipatory regulation process influenced by rates of heat storage, presumably providing some level of feedback to the brain, that is activated the moment exercise begins. This would prevent excessive heat production in hot conditions and ensure that a critical limiting body temperature is not reached prematurely during voluntary exercise. However, heart rate and RPE also were similar between hot and cool conditions in this study for both Africans and white persons; therefore, these factors also may have contributed to pace regulation. Additionally, levels of relative strain during the 30-min steady-state run that preceded the 8-km time trial were higher in white athletes, even in cool conditions. Although these differences were not significant, this is likely a result of poor statistical power (N = 6 each group), and the higher relative strain in the white athletes may have contributed to the performance differences observed. Further work is required to determine directly whether there is an anticipatory process in the brain controlling work output through feedback loops involving either rates of heat storage or perhaps cardiorespiratory strain.

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CONCLUSIONS

Although the negative impact of heat stress on exercise-heat tolerance has become commonly accepted, the underlying mechanism remains incompletely understood (Fig. 7). Hyperthermia, which has a multimodal effect on eliciting fatigue, including local effects on tissues such as skeletal and cardiac muscle not covered in the present review, is known to be a challenge to the cardiovascular system as a whole. Evidence is emerging that hyperthermia directly affects the functioning of the brain through altering cerebral blood flow and metabolism and decreasing the level of central cognitive or neuromuscular drive, which may in turn either decrease muscle function or else alter the perception of effort. Another potential mechanism of exercise impairment partially may be the result of decrements in blood flow to specific regions such as the gastrointestinal tract, producing a cascade of endotoxemia that may contribute both centrally and peripherally to fatigue or else may act on specific structures within the brain. Unfortunately, a practical and accurate method of directly monitoring brain temperature in exercising humans currently does not exist, but there is clearly a need to investigate further the effects of brain temperature on cognitive processes along with brain blood flow, metabolism, neurohumoral responses, and the subjective perception of effort during exercise. In addition, future studies should focus on isolating the effects of temperature per se on exercise performance, independent of confounding factors such as high cardiovascular strain. Hyperthermic fatigue and exhaustion is characterized by large interindividual variability, and the mechanisms underlying this variability also require further research.

Figure 7.

Figure 7.

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Acknowledgments

Supported by a Discovery Grant from the Natural Sciences and Engineering Research Council. The authors thank R. Gillingham for assistance with manuscript preparation.

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References

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Keywords:

hyperthermia; fatigue; neuromuscular activation; EEG; endotoxemia; perception of effort; critical internal temperature

©2004 The American College of Sports Medicine