Heat, Hydration and the Human Brain, Heart and Skeletal Muscles

Physical work capacity and endurance exercise performance are typically impaired in high ambient temperatures, particularly when accompanied by whole-body hyperthermia [4, 10, 14‐19]. Galloway and Maughan, for instance, observed a ~ 45% decline in time to exhaustion when ambient air temperature was increased from 11 to 31 °C [15], a finding in agreement with other studies in the literature [15, 16, 20]. Submaximal endurance performance can be markedly degraded in the heat even with only a modest increase in core temperature [18, 21‐23], suggesting a potential role of skin hyperthermia in the fatigue process. Dehydration, a natural consequence of body water losses through sweating, can compound the impairment in physical performance, but its impact is minimal when environmental temperature is low. In support of this idea, Kenefick and colleagues found that dehydration of 4% body mass reduced cycling time trial performance by up to ~ 23% in a hot environment (40 °C; no fan cooling), but the performance decrement was diminished to 12%, 5% and 3% when the ambient temperature was decreased to 30 °C, 20 °C and 10 °C, respectively [10]. The greater impact of dehydration on submaximal endurance performance in high compared to low ambient temperature is generally reflected in the available literature, where endurance performance shows little or no decrease in cooler conditions [10, 11] compared to much hotter and uncompensable environments [9, 24, 25] (see [12] for review). Interestingly, whole-body aerobic metabolism (\(\dot{V}{\text{O}}_{2}\)) remains at control levels during submaximal endurance exercise, despite evident physical performance degradation [26]. In addition, changes in substrate utilisation do not appear to impair aerobic exercise performance (e.g. time trial) [31] even though progressive dehydration [27‐29] and hyperthermia [30] lead to enhanced carbohydrate oxidation and muscle glycogen utilisation.

While submaximal endurance performance can be markedly impaired without significant reductions in whole-body \(\dot{V}{\text{O}}_{2}\), both maximal aerobic capacity (\( \dot{V}{\text{O}}_{2\text{max} } \)) and maximal endurance performance can be suppressed to a varied extent when performing in the very heavy and severe exercise intensity domains. Studies comprehensively exploring the independent and combined effects of body hyperthermia and dehydration on \( \dot{V}{\text{O}}_{2\text{max} } \) support this idea. In some cases heat stress only minimally reduces \( \dot{V}{\text{O}}_{2\text{max} } \) (≤ 3%) and endurance performance [1, 32], whereas in others, more substantial (~ 7–30%) impairments are shown [4, 5, 22, 33‐38]. For example, Arngrimsson and colleagues found that \( \dot{V}{\text{O}}_{2\text{max} } \) was reduced by ~ 4%, ~ 9% and ~ 18% during constant-load treadmill running at 35 °C, 40 °C and 45 °C ambient temperature, respectively. Of note, the fall in \( \dot{V}{\text{O}}_{2\text{max} } \) in the highest ambient temperature (i.e. 45 °C) was halved when the same exercise was performed without any preceding warm-up, suggesting that the combination of high internal (core) and skin temperature is an important prerequisite for a reduced maximal aerobic capacity. Their study, however, did not partition the effects on \( \dot{V}{\text{O}}_{2\text{max} } \) of skin hyperthermia and whole-body hyperthermia.

To characterise the independent effect of skin hyperthermia in conditions requiring maximal aerobic capacity, a recent study carefully manipulated body temperature with a water-perfused suit to investigate the impact of high skin temperature without an increase in core temperature on \( \dot{V}{\text{O}}_{2\text{max} } \) and work capacity in endurance-trained cyclists [38]. In this study, participants performed three incremental exercise tests to volitional exhaustion with (1) skin hyperthermia (T_sk + 6 °C), (2) whole-body hyperthermia (T_sk + 6 and T_core + 1 °C) or (3) control temperatures. Whole-body hyperthermia resulted in a similar average reduction in maximal work rate (~ 13%) and \( \dot{V}{\text{O}}_{2\text{max} } \) (~ 8%) to that seen in the existing literature. Importantly, skin hyperthermia alone did not compromise work or aerobic capacity, with maximal work rate and \( \dot{V}{\text{O}}_{2\text{max} } \) attaining equivalent values to those seen during the control trial. In contrast to these recent findings, others have found a weak or non-existing relationship between the reduction in \( \dot{V}{\text{O}}_{2\text{max} } \) and high core temperature, fuelling support for the hypothesis that high skin blood flow requirements in the heat are a predominant factor reducing maximal aerobic capacity [1, 5, 39]. This theory is based on the evidence in untrained and unacclimated individuals that the impaired \( \dot{V}{\text{O}}_{2\text{max} } \) in the heat compared to a cool environment was associated with a ~ 1.2 L min⁻¹ lower maximal cardiac output (\(\dot{Q\ }\)) [1]. By extension, the lower maximal \(\dot{Q\ }\) was purported to be related to substantial elevations in skin blood flow [5]. Two observations in trained individuals argue against the skin hyperthermia hypothesis: (1) skin hyperthermia does not seem to alter general physiological function (i.e., active tissue blood flow and metabolism) compared to control conditions [38], and (2) \( \dot{V}{\text{O}}_{2\text{max} } \) and maximal \(\dot{Q\ }\) are not reduced below control levels [35]. Taken together, these observations indicate that, at least in trained participants, the extent of the rise in both internal and skin temperatures is an important prerequisite for the development of a considerable degree of physiological strain that results in a substantial decline in \( \dot{V}{\text{O}}_{2\text{max} } \) in hot conditions.

The magnitude of whole-body hyperthermia is also an important factor in determining whether dehydration augments cardiovascular strain (i.e., reduces peripheral and systemic blood flow and mean arterial pressure and increases peripheral vascular resistance), and ultimately compromises aerobic capacity. Dehydration does not compromise or induces only small reductions in \( \dot{V}{\text{O}}_{2\text{max} } \) and exercise performance in cool environments where humans experience much lower skin and core temperatures [40‐42]. However, when dehydration is coupled with high ambient temperatures and therefore whole-body hyperthermia becomes apparent, \( \dot{V}{\text{O}}_{2\text{max} } \) and maximal endurance performance are compromised. For example, Ganio et al. [43] discovered \( \dot{V}{\text{O}}_{2\text{max} } \) to be reduced by 8.7% when participants were dehydrated by 3.7% following 120 min of submaximal cycling in the heat [43]. When the loss in body mass was minimised (e.g. by shortening the duration of submaximal exercise), or when fluid was regularly ingested, no significant fall in \( \dot{V}{\text{O}}_{2\text{max} } \) was observed. Therefore, it seems that to negatively affect \( \dot{V}{\text{O}}_{2\text{max} } \) and maximal endurance performance the degree of dehydration should be ≥ 3% body mass loss. A word of caution is needed here, as the physiological effects of dehydration interact with those of hyperthermia and thus the magnitude of both stressors should be considered in predicting their impact on \( \dot{V}{\text{O}}_{2\text{max} } \) and maximal endurance performance.

Figure 1 illustrates the \(\dot{V}{\text{O}}_{2}\) dynamics data during constant-load maximal aerobic exercise reported by Nybo and colleagues [34]. In this study, endurance-trained athletes performed four cycling bouts to exhaustion at ~ 402 W in different hydration and thermal states. Hydration status was carefully manipulated during 2 h of prior submaximal cycling in the heat to evoke either 4% body mass loss and hyperthermia (dehydration and hyperthermia), or maintain hydration status and normal body temperatures by ingesting fluid during exercise (euhydration control). In addition, thermal strain was manipulated with a water-perfused suit to induce low body temperatures during maximal exercise when dehydrated (dehydration alone) or skin and core hyperthermia when euhydrated (whole-body hyperthermia alone). The combination of dehydration and hyperthermia and whole-body hyperthermia alone reduced performance time by ~ 52% and \( \dot{V}{\text{O}}_{2\text{max} } \) by ~ 16% compared to the control hydrated condition (Fig. 1). When the athletes exercised in a dehydrated state, but with low body temperatures, the falls in maximal endurance capacity and \( \dot{V}{\text{O}}_{2\text{max} } \) were noticeably attenuated (~ 25% and ~ 6%, respectively). A common finding of this and previous studies is that dehydration alone can reduce maximal exercise capacity without marked reductions in \( \dot{V}{\text{O}}_{2\text{max} } \) [34, 40, 41]. The earlier fatigue when dehydrated, but ‘normothermic’, likely reflects the persistent reduction in blood volume, leading to compromised locomotor and systemic blood flow and oxygen delivery, as maximal heart rate is similar at exhaustion [34, 40, 41]. In conclusion, dehydration amounting to 3–4% body mass loss reduces physical work and endurance exercise capacity and augments the development of body hyperthermia, so that these two stressors in combination can in some conditions hinder \( \dot{V}{\text{O}}_{2\text{max} } \). Many of these studies, however, did not focus on the physiological mechanisms underpinning the reduced athletic performance. The following sections explore how dehydration and hyperthermia affect oxygen and the nutrient supply and metabolism of specific tissues of the human body and general physiological function.

Classically, stroke volume is thought to be determined by intrinsic factors within the heart itself (i.e., cardiac mechanics, contractility and filling time) and extrinsic factors associated with alterations in preload (i.e., venous return) and afterload (i.e., arterial blood pressure and peripheral vascular resistance). The contribution of these intrinsic and extrinsic mechanisms to the dehydration-induced stroke volume reduction are discussed below, starting with the intrinsic cardiac factors. Firstly, it seems that at rest and during exercise of a low cardiovascular demand, when \(\dot{Q\ }\), mean arterial pressure, systemic vascular resistance, cardiac ejection fraction and left ventricle (LV) mechanics are stable, the reduction in stroke volume is unrelated to changes in LV function [54]. Measures of systolic twist and basal rotation velocity (e.g. LV mechanics) are largely maintained or somewhat enhanced by dehydration [54], similar to findings during intermittent, submaximal exercise [55]. We cannot rule out the possibility that more substantial body mass losses in combination with more prolonged, high-intensity exercise negatively affect LV function and contribute to large stroke volume decline. In this light, some evidence suggests a depressed regional strain, torsion and untwisting velocity following an ultra-endurance activity inducing a body mass loss of ~ 4.5% [56]. However, the observation that \(\dot{Q\ }\) is elevated following endurance exercise indicates that cardiac performance overall is not impaired during recovery. Moreover, the lack of effect of dehydration at rest and with low-intensity exercise [54] lends support to the argument that altered LV mechanics do not contribute to the stroke volume reduction with dehydration. Secondly, the fall in ESV with progressive dehydration at rest and small muscle mass exercise is indicative of an enhanced rather than a depressed cardiac contractility [54]. Thirdly, the progressive reduction in cardiac filling time secondary to the increase in heart rate could contribute to the reduction in stroke volume with dehydration, as seen during prolonged submaximal exercise in the heat [50, 57, 58]. The increase in heart rate is a response to reduced blood volume, and elevations in core temperature and sympathoadrenal activity [48, 59]. The contribution of cardiac tachycardia to the reduced stroke volume with dehydration is backed by the observations that (1) raising heart rate, by right atrial pacing, leads to reductions in stroke volume at any given exercise intensity [60], and (2) use of β1-adrenergic blockade during prolonged exercise prevents both the normal increase in heart rate and the normal reduction in stroke volume, probably because of the relatively longer diastolic filling time [50, 57]. Hence intrinsic factors such as cardiac contractility and mechanics do not seem to be the mechanisms explaining the stroke volume decline with dehydration and hyperthermia, but the reduction in filling time accompanying the ensuing tachycardia is an important factor.

On the other hand, the role of extrinsic factors in the stroke volume decline can be examined by scrutinising the mean arterial pressure and LV volume responses. Augmented afterload is not a factor as progressive dehydration lowers arterial pressure [48]. Instead, the diminished LV end-diastolic volume and lowered femoral beat volume indicate that venous return is compromised in conditions of dehydration and hyperthermia [26, 54]. The lower circulating blood volume resulting from the water losses via sweat and the enhanced peripheral vasoconstriction are two factors associated with the lesser venous return and left ventricular filling. These observations challenge the idea that the decline in \(\dot{Q\ }\) causes the reduction in peripheral blood flow. On the contrary, it seems based on the responses of the different components of Ohm’s law that peripheral mechanisms restricting blood flow and thus venous return to the heart might account for most of the \(\dot{Q\ }\) decline with dehydration and hyperthermia [60] (see further discussion in section 4). Although this hypothesis warrants further investigation, the evidence reviewed here disputes a dominant cardiac limitation, and instead suggests that the cardiac stroke volume decline with dehydration and hyperthermia at rest and during exercise is to a large extent the result of the reduced ventricular filling owing to lower venous return and filling time.

Several local and central regulatory mechanisms may explain these differential limb haemodynamic responses to dehydration under resting and different exercise conditions. The limb blood flow responses to small muscle mass and whole-body exercise with varied hydration status can be interpreted using Ohm’s law, as the net consequence of alterations in either perfusion pressure, local vascular conductance or both. The main determinant of limb vascular conductance, the inverse of resistance, is the change in diameter of the resistance arterioles located in the muscle microcirculation. A decrease in limb vascular conductance is indicative of vasoconstriction (decreased vessel diameter), whereas an increase indicates vasodilation (increased vessel diameter). In this construct, the small increase in limb blood flow seen in small muscle mass exercise must be due to net local vasodilation, as mean arterial and limb perfusion pressure were slightly but significantly suppressed [61]. The interplay between locally released vasodilator factors and sympathetic vasoconstrictor activity primarily regulates active muscle blood flow [70‐72]. It is possible that thermal, fluid and oxygen-sensing mechanisms activated by (1) increases in local tissue temperature similar to that observed during local and whole-body passive heating [68, 69, 73‐75], (2) reductions in cellular volume, and (3) elevations in arterial oxygen content concomitant with the dehydration-mediated haemoconcentration [61, 76] together lead to augmented vasodilator activity in the face of a very low systemic sympathetic activity (e.g. circulating noradrenaline 1.2–1.9 nmol L⁻¹). This contrasts with the responses to whole body prolonged exercise where a similar fall in mean arterial pressure (~ 8%) is accompanied by a much larger increase in circulating catecholamines (~ 18 nmol L⁻¹). Paradoxically, however, vascular conductance is essentially unchanged or slightly enhanced [26, 61]. This observation is similar to those seen during constant-load, maximal exercise with superimposed body hyperthermia [35]. Taken as a whole, these findings (based on whole limb vascular conductance data) suggest that there is little or no role for actual vasoconstriction in the reduced exercising muscle blood flow with dehydration and hyperthermia during whole body exercise, but rather this is a passive event caused by the overall circulatory strain and manifested in conditions of high physiological load. Regardless of the mechanism, the large fall in active-muscle perfusion during strenuous whole-body exercise can reduce O₂ supply, which is initially compensated by increases in oxygen extraction, but in conditions requiring near or maximal aerobic capacity would eventually lead to compromised local and systemic aerobic metabolism and accelerated fatigue, as discussed in section 6 [34, 35].

The compromised CBF seen during exercise in the heat, with and without dehydration, is coupled with a fall in cerebrovascular conductance [108]. The precise regulation of cerebrovascular tone is inherently complex, potentially involving many different respiratory, metabolic and neural signals [109, 110]. The combination of hyperthermia, dehydration and strenuous exercise augments circulating noradrenaline; however, the direct effect of enhanced sympathetic vasoconstrictor activity on the cerebral vasculature is as yet unclear [111]. A more likely candidate explaining the fall in CBF in the hyperthermic and dehydrated athlete is the hyperthermia-induced hyperventilation and concomitant lowering of the partial pressure of arterial CO₂ (P_aCO₂) [100, 108]. Progressive reductions in P_aCO₂ reduce CBF in the resting human [112] and account for all of the reduction in CBF during severe passive hyperthermia [113, 114]. A reduced P_aCO₂ also plays a prominent role in the fall in CBF during prolonged exercise in the heat [100], and with superimposed dehydration [106]. The early fall in CBF when dehydrated is associated with a higher core temperature and hyperventilation and a greater fall in P_aCO₂ [108].

The early reductions in CBF seen during strenuous exercise in the heat, with and without dehydration, have been postulated to reduce cerebral oxygenation [115]. A lower vascular and neuronal oxygenation could potentially compromise the cerebral metabolic rate for oxygen (CMRO₂), thereby contributing to the overall process of fatigue [115], reductions in motor output [116, 117] and reductions in cognitive performance [118‐121] that are magnified in hot environments and/or when dehydrated [118, 122‐124]. The characterisation of the CMRO₂ dynamics during exhaustive exercise is therefore a key question in integrative human physiology. CMRO₂ is calculated using the Fick principle, as CBF × the arterial-to-jugular venous O₂ content difference (or O₂ extraction). The available, albeit limited, data indicate that CMRO₂ is largely unaltered from rest-to-moderate intensity exercise [82, 83, 87], before seemingly increasing close to maximal intensities [107, 115, 125, 126]. It could be anticipated that the accelerated reductions in CBF seen with dehydration and hyperthermia during exercise in the heat would be accompanied by a decrease in the CMRO₂. However, the available evidence does not support this idea. In two studies, CMRO₂ appears to even increase during exhaustive exercise, as the increase in cerebral O₂ extraction was greater than the fall in CBF (up to ~ 32% vs. ~ 15–20%) [104, 107]. The increase in CMRO₂ was postulated to be due to the substantial core hyperthermia and related Q₁₀ effect, and the heightened ‘cognitive’ effort to maintain the required physiological output when exercising in the heat. Further supporting that CMRO₂ is not compromised, we recently observed a maintained CMRO₂ during exercise in the heat across a range of exercise intensities and hydration states (Figs. 3 and 4). However, we did not see the previously reported increase during exhaustive exercise, as the CBF reductions and the compensatory increases in cerebral O₂ extraction were proportional. The differential CMRO₂ responses (increased vs. maintained CMRO₂) are likely due to methodological differences in the calculation of CMRO₂, specifically, whether CBF is obtained globally by the Kety–Schmidt method [104], or regionally using assumed values [107]. It is likely that global CMRO₂ is underestimated when CMRO₂ is quantified using oxygenation values measured in the internal jugular vein, and in our case volumetric CBF was only measured in the internal carotid artery (ICA; perfusing ~ 75–80% of the brain) [106, 108], which could be somewhat different to the responses of the posterior cerebral circulation [92, 95]. Ideally, blood flow in the vertebral arteries (accounting for the remaining ~ 20% of CBF) and oxygenation in the vertebral veins should be assessed simultaneously [127]. Notwithstanding these limitations, these studies consistently show a large cerebral O₂ extraction reserve and a maintained or enhanced CMRO₂, even in the most strenuous of exercise conditions, and therefore a reduced global cerebral oxygen metabolism is unlikely to explain the early fatigue seen in hot conditions while in the dehydrated and/or hyperthermic state.

The severe physiological strain induced by significant dehydration and hyperthermia is associated with the impaired submaximal endurance capacity in athletes and is typified by marked declines in blood flow to active skeletal muscle, skin and brain and \(\dot{Q\ }\), a substantial increase in total peripheral resistance and a small reduction in mean arterial pressure or perfusion pressure (Fig. 5) [26, 45, 48, 49]. The reduction in \(\dot{Q\ }\) is primarily related to the lowering in stroke volume, owing to the hyperthermia-induced cardiac tachycardia [48, 50, 57, 58] and concomitant reductions in blood volume and venous return [17]. The latter is related to peripheral vasoconstriction occurring in the brain, active skeletal muscle, skin and perhaps other upper body organs and tissues such as visceral organs. Lower tissue blood flow is related to the interaction between increases in vasoconstrictor activity (including sympathetic nerve activity) and alterations in vasodilator activity, although their specific contributions are as yet unknown [72]. Notwithstanding, the reductions in systemic, brain, locomotor limbs, skin and upper body tissues and organs blood flow and O₂ supply are compensated for by increases in tissue O₂ extraction, such that whole body \(\dot{V}{\text{O}}_{2} \) is preserved [26]. The development of fatigue, when dehydrated and hyperthermic, during prolonged submaximal exercise is associated with the attainment of near to maximal heart rate and an augmented internal body temperature [45, 48, 130], the latter with implications for the central nervous system [131]. However, identifying the precise mechanism is challenging, given the multitude of circulatory, respiratory, perceptual and central processes, occurring simultaneously, that interrelate to advance fatigue [12, 13].

Figure 6 outlines how the severe physiological strain induced by significant dehydration and hyperthermia impairs exercise capacity at intensities close to or at \( \dot{V}{\text{O}}_{2\text{max} } \). In accordance with the Fick principle, the maximal convective O₂ transport and O₂ extraction (a-vO_2diff) set the upper limit for local tissue and systemic \(\dot{V}{\text{O}}_{2}\). Systemic, active skeletal muscle and brain O₂ delivery are markedly suppressed during high-intensity exercise to volitional exhaustion [35, 95, 107, 132, 133] and, as outlined in sections 4 and 5, the early fatigue with dehydration and hyperthermia is associated with a faster decline in peripheral blood perfusion. The early attenuation in the rate of O₂ delivery is temporally associated with the attainment of the limit of functional O₂ extraction reserve (~ 90%) across the locomotor limbs, with the consequence that active skeletal muscle \(\dot{V}{\text{O}}_{2}\) and \(\dot{V}{\text{O}}_{{2{\text{max} }}}\) are blunted [35, 38]. Contrastingly, the brain does not appear to attain the limit of its functional O₂ reserve at exhaustion (~ 40%) and, despite a marked fall in CBF, CMRO₂ is preserved [108]. The decline in \(\dot{Q\ }\) seen during maximal exercise, with and without hyperthermia and dehydration, is due to reductions in stroke volume (SV). In the context of the dehydrated and hyperthermic athlete exercising at maximal intensities, the fall in SV might be related to the reduction in EDV, owing to reductions in blood volume and the diminished venous return paralleling peripheral vasoconstriction (Fig. 6).

The two scenarios presented above show that the combination of dehydration, hyperthermia and exhaustive exercise leads to considerable physiological strain underpinning functional alterations in multiple organs and tissues, which directly or indirectly could curtail exercise capacity. But as discussed in Sect. 3, 4 and 5, there are numerous conditions whereby global reductions in heart, active skeletal muscle and brain O₂ delivery and tissue metabolism do not explain the development of fatigue. For instance when exercise intensity is low, or involves a small proportion of the total muscle mass, dehydration can reduce exercise duration [134], unrelated to reduced O₂ delivery, \(\dot{V}{\text{O}}_{2}\) or the accumulation of muscle metabolites [52, 54, 61, 134]. Moreover, physiological function is largely preserved when exercise is performed in a cold environment (~ 8–10 °C) [7, 10, 17, 135], despite reductions in plasma and blood volume that might decrease stroke volume if exercise is prolonged and intense [17]. This idea is supported by evidence that fatigue also occurs when central and peripheral haemodynamics and body temperatures are stabilised during strenuous prolonged exercise in the heat, when participants match their sweat loss with a proportional intake of fluids (Fig. 3, right-hand panel) [10, 26, 48, 49]. Thus, fatigue in exercise scenarios with apparent systemic physiological stability is likely to involve a number of local tissue, cellular and molecular mechanisms that are beyond the scope of this review, but which are comprehensively discussed elsewhere [136].