Pathophysiology of Heat-Related Illnesses

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Chapter 10 Pathophysiology of Heat-Related Illnesses

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The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Army or the Department of Defense.

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Heat illnesses are best viewed as existing along a continuum, transitioning from the mild conditions of heat cramps and heat exhaustion to the life-threatening condition of heatstroke. Environmental heat exposure is one of the most deadly natural hazards in the United States, with approximately 200 heatstroke deaths per year. Although the majority of heatstroke deaths are observed in vulnerable populations during annual heat waves, young fit individuals may also succumb to heatstroke while engaging in strenuous activities such as athletic competitions, military operations, or occupational tasks. Multiorgan system failure is the ultimate cause of heatstroke death, and there is a complex interplay among the physiologic and environmental factors that compromise an individuals’ ability to adequately respond to heat stress. The pathophysiology of heatstroke is thought to be caused by a systemic inflammatory response that occurs in response to endotoxin leakage from the gut, but there remains limited understanding of the mechanisms that mediate morbidity and mortality. This chapter provides an overview of the pathophysiologic responses that are observed in patients and experimental animal models at the time of heatstroke collapse and during long-term recovery. A brief discussion is provided on current clinical heatstroke treatments and promising avenues of research that may aid in the development of more effective interventions and/or treatments to prevent this debilitating illness.

Heat Stress and Thermoregulation

Four Avenues of Heat Exchange

Mammals and other homeotherms are capable of maintaining body temperature within a fairly narrow range (approximately 35° to 41° C [95° to 105.8° F]) despite large fluctuations in environmental temperature. Environmental variables that have the largest impact on heat exchange are temperature; humidity; radiation from the air, water, or land; and air or water motion.88 To maintain stable body temperature, organisms rely on four avenues of heat exchange: conduction, convection, radiation, and evaporation.

Dry heat exchange is achieved by conduction, convection, and radiation. The effectiveness of these mechanisms depends on differences between the skin and environmental temperatures. That is, dry heat loss occurs when skin temperature exceeds that of the environment, and dry heat gain occurs when environmental temperature exceeds that of the body. Conduction occurs when the body surface is in direct contact with a solid object and depends on the thermal conductivity of the object and the amount of surface area in contact with the object. Conduction is typically an ineffective mechanism of heat exchange because of behavioral adjustments that minimize contact with an object. For example, the wearing of shoes is an effective behavioral adjustment that minimizes conduction of heat from a hot surface (e.g., desert sand to the foot). Within the body, conductive heat transfer occurs between tissues that are in direct contact with one another, but is limited by poor conductivity of the tissues. For example, subcutaneous fat has approximately 60% lower conductivity than does the dermis and impedes conductive heat loss.332 Convection is a mechanism of dry heat transfer that occurs as air or water moves over the skin surface. The windchill index is an example of the convective cooling effect of wind velocity. The rate of convective heat transfer depends on the temperature gradient between the body and environment, thermal currents, bodily movements, and areas of the body surface that are exposed to the environment, which can vary dramatically with different clothing ensembles. Within the body, convective heat transfer occurs between blood vessels and tissues and is most efficient at the capillary beds, which are thin-walled and provide a large surface area for heat exchange. Radiative heat transfer is electromagnetic energy that is exchanged between the body and surrounding environmental objects and is independent of air velocity or temperature. It is effective even when air temperature is below that of the body. All objects within our environment absorb and emit thermal radiation, but clothing can reduce radiant heat that impinges on the skin from various environmental sources.

Evaporation represents a major avenue of heat loss when environmental temperatures are equal to or above skin temperature or when body temperature is increased by vigorous physical activity. In humans, evaporative cooling is achieved as sweat is vaporized and removes heat from the skin surface, with approximately 580 kcal of heat lost per each liter of evaporated sweat.94 The most important environmental variables affecting evaporative cooling are ambient humidity and wind velocity. Sweat is converted to water vapor and readily evaporates from the skin in dry air with wind, whereas the conversion of sweat to water vapor is limited in still or moist air. If sweat accumulates and fails to evaporate, sweat secretion is inhibited and the cooling benefit is negated. Small mammals, such as rodents, do not possess sweat glands but achieve evaporative cooling by grooming nonfurred and highly vascularized skin surfaces, such as the ears, paw pads, and tail, with saliva that evaporates in a manner similar to that of sweat in humans.104,294

Body Temperature Control

Regulation of a relatively constant internal temperature is critical for normal physiologic functioning of tissues and cells because membrane fluidity, electrical conductance, and enzyme functions are most efficient within a narrow temperature range. By convention, thermal physiologists describe body temperature control with a two-compartment model that consists of an internal core (i.e., viscera and brain) and an outer shell (i.e., subcutaneous fat and skin) (Figure 10-1).70


FIGURE 10-1 Distribution of temperatures within the human body into core and shell during exposure to cold and warm environments. The temperatures of the surface and thickness of the shell depend on the environmental temperature: the shell is thicker in the cold and thinner in the heat.

(From Elizondo RS: Human adaptation to hot environments. In Rhoades RA, Pflanger RG, editors: Human physiology, ed 3, Philadelphia, 1996, Saunders. Reprinted with permission of Brooks/Cole, a division of Thomson Learning.

The skin is the final barrier between the body and the environment and functions as a conductive pathway for heat transfer to the environment, while also serving as the primary site to sense changes in environmental temperature. Skin temperature may fluctuate because of changes in environmental temperature, relative humidity, wind velocity, and radiation. Heat-transfer mechanisms are evoked in response to changes in body heat storage (S), which depends on metabolic rate, work, and the four avenues of heat exchange, as follows:


where M is metabolic rate, W is work, and E, C, K, and R are evaporative, convective, conductive, and radiant heat transfer, respectively.132 The impact of the four avenues of heat exchange on total body storage depends on a variety of organismal (e.g., age, gender, adiposity), environmental (e.g., humidity, wind velocity), and occupational (e.g., protective clothing, work intensity) variables. Under conditions in which heat production and/or heat gain exceeds heat loss, such as during exercise or heat exposure, positive heat storage occurs and body temperature increases. When heat loss exceeds heat production and/or heat gain, such as during prolonged cold exposure, negative heat storage occurs and body temperature decreases.88

Endothermic animals use both autonomic and behavioral thermoeffector mechanisms to regulate body temperature. Autonomic thermoeffector responses are often referred to as “involuntary” and include sweating, vasodilation, vasoconstriction, piloerection (furred mammals), and shivering and nonshivering thermogenesis (brown fat heat production). Behavioral thermoeffector mechanisms are considered “voluntary” and include clothing changes, use of heat or air conditioning systems, huddling or use of blankets, fan cooling, and seeking of shade or shelter. Rather than working independently of one another, autonomic and behavioral thermoeffector mechanisms typically function in concert to maintain temperature control. For example, evaporative cooling in rodents requires autonomic stimulation of salivation and behavioral spreading of saliva onto nonfurred surfaces.104,294 Many large species in the wild use natural water sources to facilitate cooling. Elephants spray water onto their skin surface, and hippopotamuses and other species are often observed near or in watering holes. Water is a more effective medium to facilitate convective heat transfer than air, because of its high heat-transfer coefficient (approximately 25 times greater than air),305 even if the water temperature is tepid. However, voluntary suppression of behavioral mechanisms of cooling in humans can increase the risk for thermal injury. This is illustrated by older adults who refuse to use air conditioning systems or leave their residences during heat waves, or highly motivated athletes and military personnel who voluntarily dehydrate and/or sustain a high rate of work in hot weather.

Regulation of body temperature is best conceptualized as a negative-feedback system consisting of sensors, integrators, and effectors. In vertebrates, neurons in the skin, spinal cord, and abdomen sense thermal stimuli and convert those signals to action potentials that are transmitted by afferent sensory neurons to the preoptic area of the anterior hypothalamus (POAH). The POAH is considered the main central nervous system (CNS) site for thermoregulatory control because it receives and integrates synaptic afferent inputs and evokes corrective autonomic and behavioral thermoeffector responses for body temperature regulation.28 A diagrammatic representation of this negative-feedback loop is shown in Figure 10-2.

The concept of a temperature set point was developed as a theoretical framework to examine regulated and unregulated changes in body temperature.19 The temperature set point is analogous to a thermostat that controls a mechanical heating device; under homeostatic conditions, body temperature is approximately equal and oscillates around the temperature set point. Environmental perturbations, such as heat and exercise, cause body temperature to deviate from the set-point temperature as heat gain and/or production exceeds heat loss and the organism becomes hyperthermic (body temperature is greater than the set-point temperature). During prolonged cold exposure, heat loss exceeds heat gain and/or production and the organism becomes hypothermic (body temperature is less than the set-point temperature) (Figure 10-3).

Regulated increases and decreases in the temperature set point are referred to as fever and regulated hypothermia (also called anapyrexia), respectively, and are protective immune responses to infection, inflammation, or trauma. Fever is defined as a regulated increase in the temperature set point and is actively established and defended by heat-producing (e.g., shivering and nonshivering thermogenesis) and heat-conserving (e.g., peripheral vasoconstriction, huddling to reduce exposed body surface area) thermoeffectors (see Figure 10-3).132 An individual is considered normothermic once fever is established and body temperature oscillates around the new elevated temperature set point (see Figure 10-3). The highly regulated nature of fever was first suggested by Liebermeister in the 1800s when it was observed that individuals actively reestablished an elevation in body temperature following experimental warming or cooling.180,286 Fever is a protective immune response used by invertebrates, fish, amphibians, reptiles, and mammals to survive infection or injury.* The protective effects of fever are mediated by increased mobility and activity of white blood cells,218,313 increased production of interferon (IFN; antiviral and antibacterial agent) antibodies,64 and reduced plasma iron concentrations, the effects of all of which inhibit the growth of pathogens.89,156 In mammals, inhibition of fever using antipyretic drugs (e.g., aspirin) increases mortality from bacterial and viral infections, which speaks to the importance of fever as an immune response.126,315

Many species also develop regulated hypothermia to survive severe environmental insults. Regulated hypothermia is elicited in response to a decrease in the temperature set point and is actively established and defended by behavioral and autonomic heat-loss mechanisms.132 The Q10 effect states that each 10° C (18° F) change in body temperature is associated with a twofold to threefold change in enzymatic reaction rates. Based on this relationship, a regulated decrease in body temperature is thought to protect against injury and inflammation by reducing production of harmful enzymatic end products that compromise tissue function under conditions of low oxygen supply. In bumblebees, infected worker bees spend significantly more time in cooler temperatures outside of the nest than healthy worker bees; this cold-seeking behavior is associated with increased survival from parasitic infection.118,213 Mice inoculated with influenza virus also show cold-seeking behavior and develop regulated hypothermia, which is associated with improved infection outcome.153 Other environmental insults that induce regulated hypothermia in small rodents include hypoglycemia,34,98 hypoxia,194,252 hemorrhage,119 dehydration,129 infection,153,176,264 and heatstroke.173,174

Mechanisms of Heat Dissipation During Thermal Stress

Cardiovascular mechanisms have evolved to shunt warm blood from the body core to the skin surface and increase heat loss during thermal stress. Arteriovenous anastomoses (AVAs) are collateral connections between adjacent blood vessels that increase the volume of blood that is delivered to a particular tissue. Mean skin blood flow can vary approximately 10-fold in humans depending on the thermal environment. The hands and feet are concentrated with AVAs that serve as effective areas for dry heat loss. The nonfurred surfaces of small rodents, such as the ears, tail, and paw pads, also have an abundance of AVAs and a large surface area to facilitate convective heat transfer.92,99 During exercise heat stress, increased blood flow to the skin surface is accompanied by sweat secretion. The density, secretion rate, and activation threshold of regional sweat glands determine the volume of sweat loss at a body site. In humans, the back and chest have the highest sweat rates for a given body temperature change, whereas only approximately 25% of total sweat is produced by the lower limbs.217 Additional factors affecting sweat rate include clothing characteristics, environmental conditions, and rate of metabolic heat production. Panting is an effective method of evaporative heat dissipation in large animals, such as birds, dogs, sheep, and rabbits, and occurs at a resonant ventilation frequency that requires minimal energy expenditure.107,257,329 Humans and rodents do not pant per se, but breathing frequency and minute volume increase during severe heat exposure to facilitate evaporative cooling from the respiratory surfaces. In humans, the contribution of respiratory evaporative cooling is small compared with that of skin evaporative cooling (Figure 10-4).

Dehydration and Electrolyte Imbalance

Water requirements during heat exposure are primarily determined by a person’s sweat losses. Water depletion dehydration develops when the rate of water replacement is not adequate, which can be a result of a mismatch between fluid intake and sweat loss, lack of water availability, or use of diuretic medications. Sweat rates may range from 0.3 to approximately 3 L/hr during athletic or occupational activities, depending on the environmental conditions and type, duration, and intensity of work.47,143 If high sweat rates are maintained without adequate replenishment of lost water, this can cause electrolyte imbalances that impede the efficiency of autonomic mechanisms of thermoregulatory control. For example, hyperosmolarity alters heat responsiveness of warm-sensitive neurons in the POAH and limits the effectiveness of evaporative heat loss.121,219,276 Severe hypernatremic dehydration is associated with brain edema, intracranial hemorrhage, hemorrhagic infarcts, and permanent brain damage (Figure 10-5, online).214


FIGURE 10-5 Effect of reduced plasma volume or increased osmolality on the sweat rates of six individuals.

(Modified from Sawka MN, Young AJ, Francesconi RP, et al: Thermoregulatory and blood responses during exercise at graded hypohydration levels, J Appl Physiol 59:1394, 1985.)

Severe reductions in electrolytes can have a profound impact on heatstroke outcome. Symptomatic hyponatremia (decreased serum sodium concentration) is a relatively rare condition, but it has been observed in marathon runners and military recruits during training exercises as a consequence of overconsumption of hypotonic fluids with inadequate replacement of sodium losses.210,230 Intracellular swelling is a severe consequence of hyponatremia that may cause CNS dysfunction. Hypokalemia (decreased serum potassium concentration) may be caused by overproduction of aldosterone, excessive sweating, or respiratory alkalosis. Any cause of overproduction of urine (polyuria) potentially causes urinary potassium loss.323 Potassium is a potent vasodilator of blood vessels to the skeletal and cardiac muscles, so excessive loss of this electrolyte can have detrimental effects, such as decreased sweat volume, cardiovascular instability, and reductions in muscle blood flow that predispose to skeletal muscle injury (i.e., rhabdomyolysis).158,279

Heat Illnesses

Heat illnesses are best viewed as existing along a continuum that transitions from the mild conditions of heat cramps and heat exhaustion to more serious conditions of heat injury and heatstroke (Table 10-1).

TABLE 10-1 Heat Illness Symptoms and Management

Condition Symptoms Management
Heat cramps Brief, painful skeletal muscle spasms Rest; replacement of electrolytes; avoid salt tablets
Heat rash (miliaria rubra) Blocked eccrine sweat glands Cool, dry affected skin area; topical corticosteroids, aspirin
Heat exhaustion Mild to moderate illness with inability to sustain cardiac output; moderate (>38.5° C [101.3° F]) to high (>40° C [104° F]) body temperature; often accompanied by dehydration Move supine individual to cool, shaded environment, and elevate legs; loosen or remove clothing, and actively cool skin; administer oral fluids
Heatstroke Profound CNS abnormalities (agitation, delirium, stupor, coma) with severe hyperthermia (>40° C [104° F]) Ensure an open airway, and move to a cool environment. Immediately cool to <39° C (102.2° F) using ice packs, water bath, wetting with water and continuous fanning; IV fluid administration; reestablish normal CNS function; avoid antipyretics or drugs with liver toxicity

CNS, Central nervous system; IV, intravenous.

Data from Bouchama A, Knochel JP: Heat stroke. N Engl J Med 346:1978, 2002; and Winkenwerder W, Sawka MN: Disorders due to heat and cold. In Goldman L, Ausiello DA, Arend W, et al, editors: Cecil textbook of medicine, ed 23, Philadelphia, 2007, Saunders, pp 763-767.

Heat cramps are typically brief but can cause agonizing pain in the skeletal muscles of the limbs and trunk. Cramps may be recurrent but are typically confined to the skeletal muscles that are involved in vigorous exercise in the heat. Skeletal muscle spasms in the extremities may be sporadic, but they are painful and develop most frequently in persons who are not acclimatized to physical exertion. However, heat cramps may also occur in fit athletes who are salt depleted. Heat cramps do not predispose to more serious heat illness and are not associated with complications beyond muscle soreness. The cause of heat cramps is not fully understood, but cramps are thought to occur in response to increased intracellular calcium release that stimulates actin–myosin filaments and muscle contraction. Current treatments include rest and replacement of electrolytes with fluids or salted food. Salt tablets should be avoided because they can cause gastrointestinal irritation and may stimulate excess potassium loss in the distal tubules of the kidneys.

Heat exhaustion (also referred to as heat prostration or heat collapse) is a mild to moderate form of heat illness that is associated with moderate (>38.5° C [101.3° F]) to high (>40° C [104° F]) elevations in core temperature and an inability to sustain cardiac output.335 The signs and symptoms of heat exhaustion include fatigue, dizziness, headache, nausea, vomiting, malaise, hypotension, and tachycardia with potential for collapse. Heat exhaustion can occur with or without exercise in hot environments and may progress to a moderately severe condition without associated organ damage. Heat exhaustion is often observed in older adults as a result of medications (e.g., diuretics), inadequate water intake that leads to dehydration, or preexisting cardiovascular insufficiency that predisposes to collapse. Treatment should consist of placing the individual in a recumbent position in a cool environment to normalize blood pressure. Oral fluid ingestion with electrolytes is often adequate for recovery; intravenous (IV) fluid administration may be warranted in severely dehydrated individuals.

Heat injury is a moderate to severe condition characterized by tissue (e.g., skeletal muscle) or organ (e.g., gut, kidney, spleen, liver) damage and hyperthermia (core temperature usually, but not always >40° C [104° F]).335 Heat injury may progress to heatstroke if the patient is not rapidly cooled. Heatstroke is life threatening, with the patient presenting with profound CNS abnormalities, such as delirium, agitation, stupor, seizures, or coma and severe hyperthermia (core temperature typically, but not always >40° C [104° F]).335 Reliance on a specific core temperature value for clinical diagnosis of heatstroke is ill advised, because there is wide interindividual variability in documented cases. One of the main reasons for a lack of clinical treatments for heatstroke is the complicated nature of the syndrome, because there are different classifications based on etiology and pathophysiologic mechanisms of injury. Classic (also known as passive) heatstroke occurs at rest in vulnerable individuals, such as infants and older adults. Several intrinsic factors may predispose infants to heatstroke death. These include increased surface area–to–body mass ratio (accelerates heat gain), limited effective mechanisms of thermoregulation (e.g., suppressed behavioral adjustments), increased risk for dehydration (e.g., lack of water availability), and preexisting respiratory infections. Many older individuals have preexisting conditions, such as mental illness, prescription drug use (e.g., diuretics, anticholinergics), or infections that predispose to passive heatstroke (Box 10-1).6,56,312

Exertional heatstroke (EHS) has a different etiology than classic heatstroke and affects young healthy populations that perform strenuous physical activity or work in temperate or hot weather. During exercise, approximately 80% of expended energy is released as heat that must be dissipated from the body to avoid hyperthermia. Military and athletic populations are composed of young, healthy individuals who are highly motivated to perform strenuous physical activity in hot weather, which increases the risk for EHS. A recent epidemiologic study identified a variety of factors that predispose to EHS, including gender (women greater than men), geographic region of origin (northern greater than southern states), preexisting illness, and race or ethnicity (whites greater than blacks).40 Unfortunately, exercise induces physiologic responses similar to those of heat stress, such that teasing apart the influence of these two factors in EHS is difficult.

Heatstroke Epidemiology and Risk Factors

The ability to perform strenuous work in a hot environment is inversely related to the heat stress level, which can be assessed using the wet bulb globe temperature (WBGT) index. The WBGT for indoor or outdoor environments is determined in the following manner:



where Tw is the natural wet bulb temperature, Tbg is the black globe temperature, and Tamb is the dry bulb temperature. Tbg determines the radiant heat load with a specialized thermometer that is surrounded by a 6-inch–diameter blackened sphere. The WBGT is the most widely used index to determine safe limits of physical activity and establish strategies to minimize the incidence of heat illness during military, athletic, or occupational tasks. The WBGT index does not take into consideration different clothing ensembles or exercise intensities, so the most practical and safe application of this measurement requires adjustment for these factors.

Heat waves are defined as three or more consecutive days during which the environmental temperature exceeds 32.2° C (90° F).41 In the summer of 2003, Europe experienced 22,000 to 45,000 heat-related deaths during a 2-week period in which the average temperature was 3.5° C (6.3° F) above normal.189,273 The European continent has experienced an increase in minimum daily temperatures over the last 30 years, and this trend will likely increase if average global temperatures continue to rise. A 1.4° to 5.8° C (2.5° to 10.4° F) increase in minimum daily temperatures in Europe is predicted over the next century.131,337 Most prediction models suggest that heat waves in the future will be more severe and longer in duration. Predictions based on climate variability data from the 1995 Chicago and 2003 Europe heat waves suggest that by 2090, heat waves in these cities will be 25% to 31% more frequent and last 3 to 4 days longer.203 Another prediction model suggests a 253% increase in annual heatstroke deaths in the United Kingdom by 2050.61

The impact of climate change is not equally distributed across the globe because of regional variability in thermal tolerance that influences the incidence of heatstroke mortality. A study of 11 U.S. cities showed that threshold temperatures for heatstroke mortality are higher in warmer southern cities than in cooler northern cities.53 A comparison of temperature–mortality relationships in southern Finland, southeastern New England, and North Carolina indicated that lower temperature thresholds in cooler climates are coupled with steeper temperature–mortality relationships.62 Similarly, the upper safety limits of environmental temperatures in the Netherlands, London, and Taiwan are 16.5°, 19°, and 29° C (61.7°, 66.2°, 84.2° F), respectively.192 A case study of 15 Marine recruits who collapsed from heatstroke during training exercises in South Carolina showed that 73% previously resided in northern states and that 60% of cases occurred during the second week of training during the hottest summer months.232 From 1980 to 2002, the highest EHS incidence in military recruits was in nonacclimatized individuals from northern, cold-climate states who were enlisted for less than 12 months.40 During July, many regions of the world have a WBGT index that is greater than 29° C (84.2° F), and military training often occurs in environments with a WBGT index that is greater than 35° C (95° F). During peacetime exercises, approximately 25% of fatal military EHS cases occur during the hottest summer months in recruits who have been in training camp less than approximately 2 weeks.192 Individuals from northern states are expected to be less acclimatized to hot, humid summer conditions than are those from southern states. Heat acclimatization improves thermotolerance but requires several days to weeks of exposure to similar heat stress and exercise conditions to be fully effective. This likely accounts for hot days early in the summer showing a greater impact on heatstroke morbidity and mortality than those cases occurring later in the training process, after the protective effects of heat acclimatization have been realized.105

Humanity’s impact on the landscape in conjunction with increased production of greenhouse gases may be creating the largest climate change. Urban heat islands are created in cities when vegetation is removed and blacktop roads and concrete buildings are erected. Temperatures may be 30° to 40° C (54° to 72° F) higher on asphalt roads and roof tops compared with those of the surrounding air.85 Since 1978 urban sprawl has accounted for an increase in city temperatures in southeastern Asia of approximately 0.05° C (0.09° F) per decade.343 Across the entire land mass of the United States, the surface temperature has increased approximately 0.27° C (0.49° F) per century because of changes in the land cover arising from agricultural and urban development.139 Concrete and asphalt surfaces cool slowly during the nighttime when air temperature decreases, and this increase in urban heat storage magnifies the intensity of heat exposure experienced by individuals living in concrete urban structures.49,165

Several social factors predispose older adults to heatstroke mortality, including living alone, inability or unwillingness to leave one’s home, residing on the top floor of buildings (heat rises), and annual income of less than $10,000.221 Most heat wave early warning systems emphasize use of air-conditioning systems, but availability and use of the units are limited by socioeconomic status because they are expensive to operate.56,221 A working air conditioner was the strongest protective factor against mortality during the 1999 heat wave in Chicago; fan cooling did not afford protection.221 High mortality rates were recorded in Chicago despite extensive programs to educate high-risk populations, such as advising older adults to seek cool shelters or use air-conditioning systems. Approximately 10,000 elders died during the France heat wave of 2003 primarily because of lack of air-conditioning units in residences and hospitals.63,312 In 2005, Hurricane Katrina ravaged the U.S. Gulf Coast, and electrical failures caused high heatstroke mortality of older adults confined to residences, retirement homes, and hospitals because local temperatures exceeded 43° C (109.4° F). Increases in the average human lifespan, global climate change, and use of medications that compromise cardiovascular adjustments to heat stress will necessitate increased reliance on artificial cooling systems and educational programs to prevent heatstroke deaths in vulnerable populations, such as older adults.

The high death toll of older adults because of excessive heat per se may be small compared with that caused by aggravation of a preexisting illness. Heat stress refers to environmental and metabolic conditions that increase body temperature; heat strain refers to the physiologic consequences of heat stress. Heat strain imposes large cardiovascular demands on the body. Blood flow is shunted from the viscera to the skin surface to dissipate excess heat to the environment, making cardiovascular fitness a more important factor than age in determining an individual’s susceptibility to heatstroke. Austin and Berry10 examined 100 cases of heatstroke during three summer heat waves in St. Louis and found cardiovascular illness in 84% of patients. Levine181 found heatstroke deaths to be associated with arteriosclerotic heart disease (72%) and hypertension (12%). Cardiac deficiency impedes heat loss and compromises the ability to maintain cardiac output during prolonged heat exposure, leading to circulatory collapse and death. Older individuals may have impaired baroreceptor reflex modulation, lower sweat rates, longer time to onset of sweating, and diminished sympathetic nerve discharge, all of which increase the risk for heatstroke morbidity and mortality.130,144,291 Minson and colleagues210 demonstrated that during heat exposure, older men relied on a higher percentage of their cardiac chronotropic reserve compared with younger men.

Preexisting infection or inflammation may compromise an individual’s ability to appropriately respond to heat stress and can be a complicating factor, regardless of age. Fifty-seven percent of heatstroke patients more than 65 years old had evidence of infection upon clinical admission during a Chicago heat wave in 1995.56,157 In Singapore, a young EHS victim had been ill for 3 days before heatstroke collapse.43 It has been proposed that acute illness or inflammation can cause transient susceptibility to heatstroke in young, fit individuals who exercise in the heat. For example, idiosyncratic episodes of hyperthermia were associated with acute cellulitis and gastroenteritis in soldiers exercising in the heat.39,146 Four male Marine recruits presented with viral illness (mononucleosis, pneumonia) before collapse from exertional heat illness (EHI) during training exercises associated with “the Crucible” at Parris Island, South Carolina.289 Peripheral blood mononuclear cells (PBMCs) from these recruits expressed higher levels of IFN-inducible genes than did those from controls who participated in the training event but did not collapse.289 High plasma levels of IFN-α and IFN–γ mediate flulike symptoms during viral infection and are often associated with EHI/EHS.24,289 In rats, exposure to lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, exacerbated inflammation, coagulation, and multiorgan system dysfunction from heat exposure.182 Taken together, these findings suggest that a preexisting inflammatory state compromises an individual’s ability to respond to heat stress with appropriate thermoregulatory or immune responses to prevent collapse or multiorgan system failure and death.

The annual Muslim pilgrimage to Mecca (i.e., the Hajj) is associated with high heatstroke incidence each year and provides many lessons regarding etiologic factors that increase susceptibility. The Hajj takes place in the hot desert environment of Saudi Arabia during the extreme weather months of May to September, when temperatures range from 38° to 50° C (100.4° to 122° F).151 Hot weather combined with physical exertion (first day consists of a 3.5-km [2.2-mile] jog), heavy clothing that is traditional to the region (limits heat dissipation), and an older population (approximately 50 years is an advanced age for this region) predispose many individuals to heatstroke. Clothing has a significant impact on Muslim women because they are required to wear darker clothing that covers a larger surface area of the body than does clothing worn by men.114 Medical conditions, such as diabetes, cardiovascular abnormalities, or parasitic diseases, are common.151 Heatstroke is a major concern, but heat exhaustion with water or salt depletion is also prevalent. Overcrowding and congestion impose large demands on sanitation services, as exemplified in the 1980s, when approximately 2 million people participated in the Hajj. Advances in modern technologies, such as more rapid transport to the area, will likely introduce additional factors (e.g., lack of acclimatization, increased greenhouse gas production, increased congestion) to this already complex situation.

Protective clothing is a significant predisposing factor to EHS during athletic (heavy uniforms), military (chemical protective clothing), or occupational activities (e.g., pesticide application, firefighting, and race car driving). Protective clothing often consists of multiple layers that insulate anatomic sites from heat exchange, including the skin and head.251 The wearing of protective clothing during strenuous work can quickly result in a dangerous elevation in body temperature. Fifty-one cases of EHI were observed in military trainees in San Antonio, Texas, during participation in a 9.3-km (5.8-mile) march in full battle dress uniform and boots.285 Lack of acclimatization to athletic uniforms and high environmental temperatures results in the majority of cases of EHS in athletes occurring on the second or third day of exposure to hot weather before these individuals are acclimatized to the uniforms and environmental temperatures.97,260

Pathophysiology of Heatstroke

The pathophysiologic responses to heatstroke range from those conditions that are experienced immediately following collapse to long-term changes that persist for several weeks, months, or years following hospital treatment and release. Currently more is known about the immediate heatstroke responses because clinical records document symptoms during hospital treatment. However, clinical and experimental research has seen a shift within the past decade toward a focus on understanding the pathophysiologic responses that mediate long-term injury. It is now believed that the long-term pathophysiologic responses to heatstroke are caused by a systemic inflammatory response syndrome (SIRS) that ensues following heat-induced damage to the gut and other organs.24 Following damage to the epithelial membrane of the gut, endotoxin that is normally confined to the lumen of this organ is able to leak into the systemic circulation and elicit immune responses that cause tissue injury. The thermoregulatory, immune, coagulation, and tissue injury responses that ensue during the long-term progression of heatstroke closely resemble those observed during clinical sepsis and are likely mediated by similar cellular mechanisms. Clinical records have provided an extensive database of the immediate consequences of heatstroke, whereas the majority of knowledge regarding the pathophysiologic mechanisms of heat-induced SIRS has been obtained from experimental animal studies. Although there are several gaps in our knowledge of the specific factors that predispose to multiorgan system failure, this is an exciting area of research that is expected to progress at a rapid rate because of continued advancements in experimental and genetic technologies. Figure 10-6 provides an overview of the current understanding of the pathophysiologic responses that are thought to initiate and mediate heat-induced SIRS, which will be discussed in detail here.

Body Temperature Responses

At the time of heatstroke collapse, the severity of hyperthermia varies widely between individuals, with reported core temperature values ranging from approximately 41° C (105.8° F) to 47° C (116.6° F).* During a summer heat wave in St. Louis in the 1950s, the core temperature of 100 heatstroke patients ranged from 38.5° to 44° C (101.3° to 111.2° F), with 10% of mortalities occurring below 41.1° C (106° F).10 In some instances, individuals may tolerate hyperthermia without adverse side effects. During a competitive marathon race in California, a 26-year-old man maintained a rectal temperature of 41.9° C (107.4° F) for approximately 45 minutes without clinical signs of heat illness.197 However, there are several reports of athletic, military, and occupational workers with core temperatures below 41.9° C (107.4° F) who were hospitalized, experienced permanent CNS impairment, or died from EHS (Table 10-2).

Hypothermia and fever are core temperature responses that are often observed in patients and experimental animal models during heatstroke recovery. Hypothermia is not a universal heatstroke recovery response in humans but has been anecdotally observed following aggressive cooling treatment. Hypothermia manifests as a rapid undershoot of body temperature below 37° C (98.6° F) and is thought to represent a loss of thermoregulatory control following heat-induced damage to the POAH. However, evidence in support of this hypothesis is lacking because autopsy reports and experimental animal studies have failed to detect histologic damage to the POAH despite extensive damage in other organs.174,192 Because hypothermia is not observed in all heatstroke patients, it continues to be regarded as a pathologic recovery response. In experimental animals, hypothermia is a natural heatstroke recovery response that is associated with behavioral and autonomic thermoeffector responses that support a decrease in core temperature. Mud puppies are ectothermic species that rely on behavioral adjustments, such as the selection of different microclimates, to control body temperature. Mud puppies heat shocked to approximately 34° C (93.2° F) behaviorally selected a cooler microclimate and maintained a significantly lower body temperature than did nonheated controls during 3 days of recovery.130 This study did not determine the impact of hypothermia on survival, but the association of decreased body temperature with the selection of cool microclimates indicated that this was a regulated response to a decrease in the temperature set point. Small rodents, such as mice, rats, and guinea pigs, showed reductions greater than 1.0° C (1.8° F) in body temperature that were associated with improved survival following passive heatstroke. In mice, hypothermia was associated with an approximately 35% decrease in metabolic heat production and the behavioral selection of microclimates that precisely regulated the depth and duration of this response.174 Exposure of mice to warm ambient temperatures that prevented heat-induced hypothermia caused increased intestinal damage and mortality.173,333 Hypothermia likely provides protection against heat-induced tissue injury in a manner similar to that shown for protection against other extreme environmental insults based on the temperature coefficient (Q10) effect.

A common heatstroke recovery response observed in patients and animal models is recurrent fever during the days and weeks of recovery.9,10,173,192,204 In mice, fever was observed within a day after passive heatstroke collapse and associated with an approximately 20% increase in metabolic heat production and increased plasma levels of the proinflammatory cytokine interleukin (IL)-6.154,172,174 IL-6 is an important regulator of fever during infection and inflammation and may regulate fever during heatstroke recovery.172 In patients, fever is reestablished following clinical cooling.192 This is reminiscent of Liebermeister’s experimental observations of the recurrence of fever following experimental cooling of the POAH of rats.180,192 In experimental animal models, the inability to recover from hypothermia and develop fever is associated with increased mortality, suggesting that fever may be important for the resolution of infection.173 However, in a case report of human heatstroke, fever was associated with poor outcome. An amateur long-distance runner was hospitalized for 10 days after collapsing from EHS during a 9.7-km (6-mile) footrace.204 Moderate fever (>38° C [100.4° F]) was evident during the first 4 days of hospitalization, but on the tenth day the patient experienced convulsions and a rapid increase of body temperature to 41° C (105.8° F). Rapid cooling and aspirin were ineffective in reducing body temperature, and the patient died.204 The inability of aspirin to inhibit the rapid rise in body temperature suggests that this was not a true fever response, but rather a pathologic response to increased metabolic heat production induced by the convulsions. It is important to recognize that there is an optimal temperature range above which the protective effects of fever are no longer realized because of the toxic effect of high body temperature on cell function.155

Immune Responses

During heat stress, blood flow to the skin is increased to facilitate heat loss to the environment and reduce the rate of total body heat storage. Increased skin blood flow is accompanied by a fall in splanchnic (i.e., visceral organ) blood flow as a compensatory mechanism to sustain blood pressure. Endotoxin is normally confined to the gut lumen by tight junctions of the epithelial membrane, but these junctions can become “leaky” following prolonged reductions in blood flow that cause ischemic stress.108,164 There are several lines of evidence that support the hypothesis that endotoxin leakage from the gut lumen into the systemic circulation is the initiating stimulus for heat-induced SIRS. First, systemic injection of LPS into experimental animals induces symptoms similar to those observed in heatstroke, including hyperthermia, hypothermia, fever, hypotension, cytokine production, coagulation, and tissue injury.175,268 Second, increased portal or systemic endotoxin levels are observed in heatstroke patients and animal models. In primates, circulating endotoxin was detected at rectal temperatures above 41.5° C (106.7° F) with a precipitous increase at approximately 43.0° C (109.4° F).90 Splanchnic blood flow shows an initial decrease at 40° C (104° F); the liver, which is an important clearance organ for endotoxin, shows damage at body temperatures of approximately 42° to 43° C (107.6° to 109.4° F).* In a young athlete with a body temperature of 40.6° C (105.1° F) on the second day of football practice, high circulating levels of endotoxin were associated with hemorrhagic necrosis of the liver.97 In heatstroke patients, endotoxin was detected at approximately 42.1° C (107.8° F) and remained elevated despite cooling.26 Third, rats rendered endotoxin tolerant following the systemic injection of LPS are protected from heatstroke mortality.66,67 The protective effect of endotoxin tolerance is related to enhanced stimulation of the liver reticuloendothelial system (RES), which is composed of monocytes, macrophages, and Kupffer cells that are important for endotoxin clearance.66,67 RES stimulation reduced and RES blockade increased mortality of heat-stressed rats.67 Fourth, antibiotic therapy protects against heatstroke in several species. In dogs, antibiotics reduced gut flora levels and improved 18-hour survival rates by more than threefold when provided before heat exposure.37 In rabbits with heatstroke, hyperthermia and endotoxemia were reduced following oral antibiotics.36 Anti-LPS hyperimmune serum reversed the heatstroke mortality rates of primates and returned plasma LPS levels to baseline, but it was ineffective at the highest body temperature of 43.8° C (110.8° F), indicating that hyperthermia can cause irreversible organ damage and death.91

Heat-induced SIRS is initiated by the innate and adaptive immune systems, which interact to sense the presence of endotoxin and orchestrate an immunologic response. The innate immune system comprises monocytes, macrophages, and neutrophils that use pattern recognition receptors (PRRs) on their cell surfaces to recognize pattern-associated molecular patterns (PAMPs) on the cell surface of endotoxin and other invading pathogens.137 Toll-like receptors (TLRs) are a class of PRRs that have been widely studied in the immune response to infection.208,314 Ten mammalian TLRs have been identified, and the specific pathogenic ligands that activate these PRRs are known (Table 10-3).

TABLE 10-3 Toll-Like Receptors of the Innate Immune System

Toll-Like Receptor Ligand Cell/Tissue Types
TLR1 Triacyl lipopeptide Monocytes, macrophages, DCs, polymorphonuclear leukocytes, B and T cells, NK cells
TLR2 Lipopolysaccharide
Lipoteichoic acid
Measles virus
Human cytomegalovirus
Hepatitis C virus
Necrotic cells
Monocytes, granulocytes
Brain, heart, lung, spleen
TLR3 Viral double-stranded RNA DCs, T cells, NK cells, monocytes, granulocytes
Placenta, pancreas
TLR4 Lipopolysaccharide
Heat shock proteins
High mobility group box 1
B cells, DCs, monocytes, macrophages, granulocytes, T cells
TLR5 Flagellated bacteria Monocytes
Ovary, prostate
TLR6 Diacyl lipopeptide B cells, monocytes
Thymus, spleen, lung
TLR7 Single-stranded RNA Monocytes, B cells, DCs
Lung, placenta, spleen, lymph node, tonsil
TLR8 Single-stranded RNA Monocytes
Lung, placenta, spleen, lymph node, bone marrow, PBLs
TLR9 CpG DNA B cells, DCs
Spleen, lymph node, bone marrow, PBLs
TLR10 Unknown B cells
Spleen, lymph node, thymus, tonsil

CpG, Deoxycytidylate-phosphate-deoxyguanylate; DC, dendritic cell; DNA, deoxyribonucleic acid; NK, natural killer; PBL, peripheral blood leukocyte; RNA, ribonucleic acid.

Data from Medvedev AE, Sabroe I, Hasday JD, et al: Tolerance to microbial TLR ligands: Molecular mechanisms and relevance to disease, J Endotoxin Res 12:133, 2006; and Tsujimoto H, Ono S, Efron PA, et al: Role of Toll-like receptors in the development of sepsis, Shock 29:315, 2008.

TLR4 is the principal receptor for LPS that stimulates gene transcription factors, such as NF-κB, to increase the synthesis of a variety of immune modulators in response to endotoxin. Endotoxin infection (i.e., sepsis) is associated with increased expression of TLR4 on circulating human PBMCs, as well as on mouse liver and spleen macrophages.307,308 In the 1960s, a spontaneous mutation in the TLR4 gene was discovered in C3H/HeJ mice, which has been an important animal model to determine the role of TLR4 in endotoxin responsiveness. C3H/HeJ mice show a diminished response to bacterial infection, but increased mortality from SIRS, because of an inability to respond appropriately to endotoxin and induce the full complement of immune responses.103 Inability to respond to antigens is known as anergy and is a proposed mechanism that predisposes to increased risk and mortality from bacterial infection.117 Given that TLR4 mutations exist in humans, this may be one (of several) genetic factors that predispose to mortality associated with heat-induced SIRS, although the association of mortality with TLR4 polymorphisms remains controversial.5,75 C3H/HeJ mice have not been tested for their resistance to heatstroke morbidity/mortality but are a useful experimental model to determine the roles of TLR4 and anergy in this syndrome.

Specificity of immune responses is provided by B and T cells of the adaptive immune system. These cells respond to antigens by secreting cytokines, which are intercellular immune signals that elicit proinflammatory (Th1 type) and antiinflammatory (Th2 type) actions during the progression of SIRS. The actions of cytokines depend on the nature of the danger signal, the target cells with which they interact, and the cytokine “milieu” in which they function. Th1 and Th2 cytokines function in a negative feedback pathway to regulate each other’s production and maintain a delicate balance of inflammatory reactions. Anergy is thought to be a consequence of inadequate Th2 cytokine production late in SIRS. For example, increased patient mortality from peritonitis is associated with the inability to mount a Th2 cytokine response.117

Alarmins are endogenous PAMPs that are released from stressed or injured tissues and initiate restoration of homeostasis following an infectious or inflammatory insult.17 High mobility group box 1 (HMGB1) is a highly conserved nuclear protein that functions as an alarmin following release from necrotic (but not apoptotic) cells.272 Necrosis is the premature death of cells in a tissue or organ in response to external factors, such as pathogens and toxins. Because necrosis is detrimental to the host, it is associated with an inflammatory response. Apoptosis refers to genetically programmed cell death that does not elicit an inflammatory response, because apoptosis is beneficial to the host. Release of HMGB1 from necrotic cells stimulates Th1 cytokine production late in the sepsis syndrome and is a purported mediator of lethality; this shift in the balance of cytokines from a Th2 to Th1 phenotype is a potential mechanism of sepsis lethality. In human PBMCs, HMGB1 interacts with TLR2 and TLR4 to enhance Th1 cytokine production in synergy with LPS.124 Elevated serum HMGB1 levels are observed 8 to 32 hours following LPS injection in mice. Anti-HMGB1 antibodies did not protect against LPS-induced mortality unless the antibodies were provided 12 and 36 hours after LPS exposure.324

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