Risk factors
No sound evidence indicates which risk factors increase EHS predisposition, but several factors have been implicated. In figure 3, we highlight the risk factors discussed in this review.
Figure 3Potential risk factors affecting exertional heat stroke. Arrow colours represent level of evidence for each risk factor: green=strong; yellow=moderate; red=anecdotal
Dehydration
No direct evidence indicates that dehydration has a causative role in EHS. But to hypothesise that it will be a risk factor is logical, given the known impact of dehydration on human physiology.70 71 Blood plasma consists of about 90% water. During exercise, because of increased metabolic demand and sweat production, plasma volume decreases, which increases plasma osmolality and blood viscosity, which are associated with increased reactive oxygen species production.72 The increased osmolality induces a pull of water from intracellular stores to extracellular stores to overcome the impact from exercise. The greater viscosity from decreased plasma volume causes cardiac drift, leading to greater cardiac strain.73 When decreases in plasma volume are drastic enough to decrease blood pressure, it can diminish cerebral blood flow and cause syncope.74 By exercising in the heat, sweat rates escalate to increase evaporative heat loss from the paired metabolic heat produced from exercise and the external environmental heat. The detriments of dehydration are exacerbated when individuals begin exercise in a hypohydrated state,75 which is frequent in athletes.76–78 In a crossover study of 17 male soldiers, Sawka et al compared heat strain between euhydrated and hypohydrated individuals with about 8% dehydration after walking for 180 minutes at 49°C and 20% humidity.79 The hypohydrated state was more responsible for heat intolerance than aerobic fitness. In the hypohydrated condition, the heart rate was higher, sweat rate was lower, and participants showed lower tolerance for temperature change (observed through exhaustion occurring at lower rectal temperature) even after heat acclimation.79 Therefore, dehydration could potentially enhance the risk of EHS via hyperthermia. While the role of dehydration in increased intestinal permeability has been hypothesised,80 more studies are needed to support this idea with EHS.
Body composition
Obesity is associated with decreased cardiovascular fitness and impaired microvascular function at the skin, potentially leading to impaired thermoregulatory responses.81 Impaired skin microvascular function could lead to a diminished ability to produce sweat that matches evaporative heat loss demands. However, an association between skin blood flow and overall thermoregulation is absent.82 In a clinical trial involving independent groups (n=9 per group), Dervis et al reported that individuals with higher fat mass have impaired sudomotor responses leading to a decreased ability to thermoregulate.83 When heat production induced by exercise was fixed, individuals with low body fat had a higher sweat rate than those with high body fat. The fact that both groups exercised at the same heat production relative to lean body mass could explain these findings. The lower lean body mass in the high fat group resulted in a lower absolute heat production and thus a lower evaporative requirement. This diminished sudomotor response could have contributed to the measured core temperature in the Dervis study being greater in the high body fat group after 60 minutes of activity than the low body fat group. Overall, the main message of Dervis study was that, once the effects of heat production and mass were accounted for, a lower average specific heat capacity of body tissues in the high fat group led to a disproportionate mean elevation in core temperature. The findings also reinforce that the thermoregulatory responses of groups with different adiposity levels should not be compared using a fixed heat production.
Adipose tissue itself is an insulator under cool conditions (about 21°C) such that high adiposity might result in decreased ability to dissipate heat and heightened risk of hyperthermia.84 Sweat evaporation is partially determined by skin temperature and varies across the body.85–87 In a clinical trial with independent groups (n=20 per group), Chudecka et al observed a statistically significant difference in skin temperature between obese and normal weight women at the thighs and abdomen—locations where excess adipose tissue is typically found in women. These findings support the concept of adipose tissue acting as an insulator, making heat dissipation in those areas less likely and causing heat retention.84 Yokota et al used a simulated heat model with six compartments (muscle, fat, vascular skin, avascular skin, core, and central blood in passive and active heat) that was based on human physiology and biophysics in male soldiers.88 The simulated model suggested that short and lean men have the greatest thermoregulatory response while tall and fat men have disadvantage in hyperthermic environments. Therefore, short and lean men were expected to wear their body armour and perform their tasks in a hyperthermic environment for 18 minutes longer than tall and fat men before reaching a core temperature of 38.5°C—a temperature in which 25% of heat casualties occur.89 This study was simply a predictive model based off collected physiological and anthropometric data in male soldiers. Yokota et al validated this same model in women. Similar to the male data, female soldiers who were short and lean were expected to cope better with required activities in hyperthermic conditions than tall-fat women.90 The researchers then had the women do the previously simulated situation and found the measured results to be consistent with the predicted results. Both Yokota studies support the idea that increased adipose tissue increases insulation, although the anatomical location of these extra fat stores and the properties of the clothing worn might also be factors.
One aspect to consider is that cutaneous blood vessels pass through the subcutaneous fat layer, thus vasodilated skin allows warm blood to bypass the subcutaneous fat layer, regardless of its thickness.91 92 The lower density of fat tissue can alter the surface area for heat dissipation, although this effect is likely small. Ultimately, regardless of the mechanism, greater body surface area probably contributes to an increased core temperature and decreased heat loss, making exertional heat illness and EHS more probable. Finally, another factor associated with obesity that might explain a greater susceptibility to EHS is inflammation. Increased adiposity is well known to cause chronic inflammation and metabolic disease,93 which are thought to be predisposing EHS risk factors.
Sex differences
Thermoregulatory differences exist between male and female individuals at high ambient temperatures in active conditions.94 95 In military populations, heat illnesses are more prevalent in women, but EHS is most common in men.96 Behavioural, hormonal, morphological, and physiological differences can be difficult to dissociate between the sexes. From a morphological perspective, variations in surface area and body composition affect thermoregulatory efficiency. Overall, male and female mammals differ in size. Absolute mass and surface area tend to be greater in male mammals whereas surface area-to-mass ratio and body fat tend to be greater in female mammals. The implications of these morphological differences between sexes to EHS responses remain unclear.97 In a preclinical model of EHS,98 female mice outperformed male mice by about 40%.59 This finding was unexpected given that this preclinical model consists of forced wheel running in uncompensable heat (37.5°C environmental temperature and 40% relative humidity) and the greater surface area-to-mass ratio in female mice.
Behavioural responses driven by endocrine stimuli could account for the higher incidence of EHS in men. Testosterone has a role in certain behaviours, including aggression and dominance,99 which could justify men’s tendency to ignore the protective physical signs and symptoms of heat illness. A clinical trial of 10 men and 10 women confirmed that, during exercise, women use thermal behaviour to a greater extent than men.100 When looking at sex specific differences, menstrual cycle fluctuations in oestrogen, progesterone, and the ratio between the two result in oscillating core temperatures,101 although the influence of menstrual cycle in thermoregulation has been limited. At least during hot and dry conditions, the menstrual cycle phase does not appear to modulate whole body heat loss during exercise.102 Oral contraceptives could affect the core temperature due to the manipulation of these sex hormones,103 however, the effect of these drugs on EHS has not been studied.
Responses to thermal stress between the sexes are primarily a result of decreased rates of metabolic heat production in female individuals.95 This decrease in metabolic heat production is presumably associated with cutaneous vascular conductance and sudomotor activity.104 105 Female individuals tend to show lower sudomotor activity at a similar heat load than male individuals, resulting in differences in temperature regulation and sweat production.94 However, in a clinical trial, Kazman et al104 compared men’s (n=55) and women’s (n=20) responses to a heat tolerance test. All women were in the follicular phase of the menstrual cycle (ie, the longest step in the menstrual cycle, lasting from the first day of a period to ovulation, when oestrogen levels are high and progesterone levels are low). In this study, women were more heat intolerant than men, as defined by a core temperature over 38.5°C, failure to plateau in body temperature, or a heart rate over 150 bpm. Thus, sex was thought to predict heat intolerance. However, a linear regression analysis found body fat percentage and VO2 max were more accurate predictors and negated the effect of sex. These findings also suggested thermal strain is less important than cardiovascular strain regarding performance in the heat.104 However, the heat tolerance test lacks sensitivity and specificity owing to its stringent terminal criteria and cannot account for fluctuations in temperature above 38.5°C106 107 and it is associated with a high fail rate of false positives.107
Oestrogen and progesterone fluctuations in the oestrous cycle result in variations in core temperature with women in the luteal phase (eg, high progesterone, lower oestrogen) showing 0.3-0.5 ◦C increase in core temperature compared with the follicular phase (eg, high oestrogen, low progesterone). Even with this variation in temperature, thermoregulatory responses did not differ throughout the estrous cycle phases. On the other hand, In a clinical trial of four women aged 20-35 years, Horvath et al observed differences in core temperature at rest that were attenuated during combined heat and exercise.108 More studies are warranted to determine the influence of sex hormones on EHS susceptibility.
Ageing
Although EHS is more prevalent in young cohorts, ageing can be considered a risk factor because it is known to hinder several thermoregulatory and cardiovascular responses. Ageing in humans is accompanied by a decrease in sudomotor function, cardiovascular function, immune function, and behavioural thermoregulation.15 These factors contribute to the increased risk of heat related morbidity and mortality.109 Elderly people typically have a higher incidence of classic heat stroke than EHS because of decreased activity levels, and many older individuals also have pre-existing cardiovascular insufficiencies, as observed by a lower VO2max, which has a negative effect on the ability to adequately respond to heat.110
Increased levels of physical activity on ageing mitigates the negative physiological alterations associated with ageing. Many factors might contribute to this impact of increased levels of physical activity, such as improved cardiovascular fitness, reduced weight, and improved immunity. The sudomotor system begins to decline considerably at age 40 years, beginning with the lower limbs and followed by the back, abdomen, upper limbs, and then head.111 The resultant decline in sweat rate is due to decreased functionality of sweat glands, and not the number of sweat glands. An age related decline in sweating limits the ability to dissipate internal (metabolic) and external (ambient) sources of heat gain causing hyperthermia and potentially collapse. With the increasing incidence of EHS beyond athletics, it is likely that humans performing daily tasks, such as lawn mowing and gardening, might be at risk of developing EHS and the impact of ageing must be taken into consideration.
Previous illness
When an organism has an immunological challenge, the innate and adaptive immune systems are activated. Innate immunity represents non-specific immunological defenses that are activated immediately after antigens appear. Adaptive immunity is an antigen specific immune response that requires recognition of the antigen and development of immune cells specific to destroying that antigen. Heat stress and EHS have been shown to degrade gut integrity and stimulate the immune system.112 113 The degradation in gut integrity is implicated in a catastrophic immune response known as systemic inflammatory response syndrome.114 Heat exposure induces a set of proteins that modulate the immune response to resolve systemic inflammatory response syndrome. Cytokines are immune modulators that have a dynamic nature and have been associated with fatalities from heat stroke. However, as previously mentioned with interleukin 6, some cytokines have been implicated in both proinflammatory and anti-inflammatory functions, which could be a function of their concentration or the surrounding milieu in which they are functioning.115 Because of the vast array of cytokines and their diverse functions, understanding which specific set of cytokines can reduce or accentuate the effects of EHS has been difficult, and is likely to involve a coordinated response among several different cytokines.62 116 Another important set of immunological cells involved in heat stroke are lymphocytes.117 118 In classic heat stroke, T regulatory cells have been shown decrease in number and in immunosuppressive function.117 When lymphocyte production is compromised, heat stroke severity is exacerbated.118 Other factors might also come into play when determining how EHS or heat stress modulate the immune response, such as thermosensors, pre-existing conditions, previous illnesses,119 and epigenetic consequences.120 121
Innate immunity is altered in individuals with comorbidities and pre-existing conditions, thus increasing the potential for exertional heat illness and, if left untreated, death. Diabetes mellitus has been shown to disrupt immune responses that are critical to staving off fungi, toxins, parasites, viruses, and bacteria. The mechanisms that are suppressed in patients with diabetes mellitus include dysfunction of immune cells, decreases in cytokine production, dysfunction in phagocytosis, and a decreased ability to eliminate microbials.122 These effects are prevalent owing to the hyperglycaemic environment in patients with diabetes mellitus.123 In terms of heat stress, hyperglycaemic environments are strongly associated with reductions in skin blood flow and sudomotor function, potentially incapacitating evaporative heat loss.124 125 Another deleterious effect of hyperglycaemic is the loss of nitric oxide availability, contributing to vascular complications.126 Based on the available evidence, a possible interplay could exist between the cardiovascular system, immune system, and diabetes—which complicates how to treat this condition and determine who is most vulnerable and why.