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Compendium July 2013 (Vol 35, No 7)

Heatstroke: Thermoregulation, Pathophysiology, and Predisposing Factors

by Carey Hemmelgarn, DVM, Kristi Gannon, DVM, DACVECC

    CETEST This course is approved for 3.0 CE credits

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    Abstract

    Heatstroke is a common veterinary emergency that, depending on the severity of injury, can progress to a life-threatening condition. Heatstroke can be classic (nonexertional) or exertional. Classic heatstroke develops when the body is exposed to high external temperatures, whereas exertional heatstroke is caused by strenuous exercise. Thermoregulation is the intrinsic ability of the body to maintain core body temperature within normal limits through an intricate balance of heat conservation and heat dissipation. Severe disease ensues when persistent hyperthermia causes injury to the body for which these mechanisms can no longer adequately compensate. The first stages of heatstroke are characterized by initial thermoregulation, acute phase response, and activation of heat shock proteins. The organ systems most commonly affected during heatstroke are the gastrointestinal tract and the coagulation, renal, cardiac, pulmonary, and central nervous systems.

    Heat-related illnesses are prevalent in human and veterinary medicine. Over a 9-year period, one study estimated that 55,000 human cases of heat-related illness were treated in emergency departments in the United States.1 The Hebrew University Veterinary Teaching Hospital in Rehovot, Israel, reported 40 cases of heatstroke in canine patients between 2005 and 2006.2 During summer months, all emergency-room cases should be evaluated closely for clinical signs of heatstroke. To limit the incidence of heat-related illnesses, exposure to heat should be minimized for high-risk populations with predisposing risk factors.

    Heat-related illnesses are categorized based on clinical signs and the body temperature of the patient. These illnesses range from mild to severe based on the length of heat exposure and whether the patient has any underlying predisposing factors. Heat stress is the mildest form of heat-related illness, and heatstroke is the most severe (TABLE 1). Numerous definitions have been proposed to describe the intricate disease process of heatstroke. In humans, the classic definition is a severe illness characterized by a core temperature >104°F (>40°C) and central nervous system abnormalities; however, a more thorough definition of heatstroke in humans has been proposed: “A form of hyperthermia associated with a systemic inflammatory response leading to a syndrome of multi-organ dysfunction in which encephalopathy predominates.”3 A similar syndrome has been described in veterinary patients.4

    Table 1. Categories of Heat-Related Illness

    Severity              

    Heat-Related Illness

    Core Temperature

    Clinical Signs/Definition

    Mild

    Heat stress17

    Normal

    Discomfort and physiologic strain

    Heat cramps7

    Normal

    Muscle cramps (identifiable limp or reluctance to walk) secondary to water and sodium depletion

    Heat exhaustion

    Normal to slightly increased (<40° C) or decreased

    Weakness, anxiety, and fainting

    Severe

    Heatstroke3

    Increased (>40° C)

    Central nervous system and cardiovascular depression

    There are two types of heatstroke. Nonexertional, or classic, heatstroke is caused by exposure to high external temperatures and is seen commonly in veterinary medicine. Exertional heatstroke is associated with strenuous exercise. The development of heatstroke is multifactorial and strongly influenced by environmental temperature, humidity, and current medical status of the patient.

    Physiologic Response to Heat Stress

    During an episode of heat stress, systemic and cellular compensatory mechanisms are activated to reduce the risk of hyperthermia. The main mechanisms are thermoregulation, acclimatization, acute phase response, and induction of heat shock proteins.

    Thermoregulation

    The anterior portion of the hypothalamus, known as the preoptic area, is the main organ responsible for thermoregulation.3–6 Changes in body (blood) or ambient temperature are detected by peripheral thermoreceptors, located in the skin and mucous membranes, and central thermoreceptors, located within internal structures, such as the spinal cord and abdominal visceral organs.6 Stimulation of these thermoreceptors leads to peripheral vasodilation and central vasoconstriction, effectively shunting heated core blood to the skin to facilitate heat dissipation (FIGURE 1).3,6

    The body relies on four main mechanisms to achieve heat dissipation. Conduction takes place when the body comes in contact with a cooler object and heat is transferred from the patient to the object.4 Radiation is the natural process of the body releasing heat into the environment. Convection is the transfer of heat to surrounding cooler air as it passes over the patient. The fourth mechanism, evaporation, takes place when a fluid changes into a vapor. Evaporation is achieved through perspiration in humans and panting in some veterinary patients (e.g., dogs, cats).3–5,7,8 Radiation and convection account for 70% of the total body heat loss in dogs and cats when environmental temperatures are below skin temperatures.9 With increasing environmental temperatures, these mechanisms become inefficient, and the body must rely on evaporation to maintain normothermia. Evaporation can also become ineffective when relative humidity is increased.

    Acclimatization

    Humans and animals can adapt to hyperthermia caused by high external temperatures or strenuous exercise through the process of acclimatization. Acclimatization consists of several mechanisms, including increased cardiac output and activation of the renin-angiotensin-aldosterone system. These changes result in conservation of sodium by the sweat glands and kidneys, increased glomerular filtration rate, and, in humans, the capacity to secrete sweat.3,4 Salt conservation increases water reabsorption through the kidneys, which subsequently increases circulating volume and maintains hydration. Cardiac output has been shown to increase up to 50% in the initial phases of heatstroke in human patients.10 These mechanisms are highly developed in elite athletes, including racing greyhounds and marathon runners, to increase their ability to resist rhabdomyolysis.3,4 In animals, partial acclimatization to environmental and climatic changes takes 10 to 20 days, and full acclimatization takes up to 60 days.4

    Key Points

    • The body uses four mechanisms to dissipate heat: convection, conduction, evaporation, and radiation. Radiation and convection account for 70% of total body heat loss in dogs and cats.9
    • In veterinary patients, exposure to high external temperatures within vehicles is a common scenario. In less than 40 minutes, the temperature in an automobile can reach 62.7C° (145°F) during the summer months, even in a light-colored vehicle with the windows partly opened.17
    • Endogenous or exogenous predisposing factors can increase an animal’s risk of progressing to a more severe form of heat-related illness.

    Acute Phase Response

    In addition to the hypothalamus-driven reaction, the canine body initiates an acute phase response similar to that documented in humans with bacterial infections, trauma, neoplasia, burns, strenuous exercise, heatstroke, or immune-mediated diseases.4 This response, which is a coordinated cellular reaction activated by inflammation, protects against tissue injury and promotes repair.4 It involves an intricate balance of increases in proinflammatory and antiinflammatory cytokines. Cytokines centrally mediate several actions within the body, including fever production, leukocytosis, accelerated synthesis of acute phase proteins, muscle catabolism, hypothalamic-pituitary-adrenal axis stimulation, and leukocyte and endothelial cell activation.3 Interleukin (IL)-1-β is one of the first proinflammatory mediators present in the early stages of heat stress.3,11 IL-1-β enhances monocyte cytotoxicity and increases the production of other proinflammatory mediators, such as IL-6 and tumor necrosis factor-α (TNF-α).12 IL-6 is involved in the stimulation of acute phase protein production, which inhibits the generation of reactive oxygen species and the release of proteolytic enzymes from activated leukocytes.3 IL-10 is the main antiinflammatory cytokine involved in the acute phase response. IL-10 limits the hyperinflammatory response through downregulation of T cells and is released in states of acute stress to counteract the activation of the neuroendocrine axis in the central nervous system (FIGURE 2).13 A similar inflammatory cascade is seen in patients with systemic inflammatory response syndrome (SIRS) and sepsis.

    Heat Shock Proteins

    Nearly all cells have an innate thermoregulatory compensatory mechanism for acute episodes of hyperthermia: when they are exposed to high temperatures, they produce heat shock proteins.3,14 These proteins act as “molecular guardians,” providing a protective tolerance to hyperthermia by maintaining intracellular function and structural protein integrity.3,15 Experimental studies have shown that induction of heat shock proteins reduces production of excessive proinflammatory cytokines.15 As a result, the severity of heatstroke-induced arterial hypotension, cerebral ischemia, and cerebral neuronal damage was reduced in these studies.16 Although effective, cellular protective mechanisms are limited and, when overwhelmed or impaired, contribute to the progression of heatstroke.16

    Pathophysiology

    Predisposition

    Exogenous and endogenous factors can predispose a patient to the development of heat-related illness. Predisposing factors can impair the ability to dissipate heat and/or cause increased heat production (BOX 1).8

    Exogenous factors include lack of acclimatization, confinement to an area with limited ventilation or shade, elevated environmental humidity, water deprivation, and administration of specific medications.4,8 In veterinary patients, exposure to high external temperatures in vehicles is common. In <40 minutes, the temperature in an automobile can reach 145°F (62.7°C) during the summer months, even in a light-colored vehicle with the windows partly opened.17 Medications that affect the body’s ability to respond to temperature changes include loop diuretics, β-blockers, and phenothiazines.7,8

    Box 1. Predisposing Factors for Heatstroke

    Endogenous

    • Obesity
    • Cardiovascular disease/abnormalities
    • Neurologic or neuromuscular disease
    • Thick haircoat
    • Upper airway abnormalities (brachycephalic breeds and/or laryngeal paralysis)

    Exogenous

    • Lack of acclimatization
    • Confinement with limited ventilation or shade
    • Water deprivation
    • Medications: Loop diuretics, β-blockers, and phenothiazines

    Endogenous predisposing factors are underlying medical conditions and physical traits that impair the ability to dissipate heat. Known underlying medical conditions in humans include obesity, cardiovascular abnormalities, neurologic or neuromuscular diseases, and laryngeal paralysis. Obesity can limit heat dissipation by inhibiting cutaneous vasodilation.8,18 In a recent retrospective study, obese veterinary patients with heatstroke were reported to have an increased likelihood of death.19

    Age can also serve as a predisposing factor. Elderly human patients are thought to be at a higher risk for heatstroke because of their reduced ability to sweat, impaired acclimatization, deficient voluntary control (e.g., impaired physical mobility), compromised cardiovascular response, and need for drug therapies that may affect the body’s ability to thermoregulate.8,20 Similar impairments may be present in aging veterinary patients, although no studies have been reported. The most common physical attributes that affect heat dissipation in veterinary patients include a thick, dark haircoat and congenital or acquired anatomic upper airway abnormalities, as seen in brachycephalic breeds or patients with laryngeal paralysis. A thick, dark haircoat decreases heat dissipation by adding layers of insulation and limiting effective cutaneous vasodilation.8 Brachycephalic veterinary patients can have decreased nasal turbinate surface area for evaporative cooling. Structural abnormalities, such as stenotic nares and an elongated soft palate, can create partial upper airway obstruction, further impairing heat dissipation through panting.8 As a result, hyperthermia is a common sequela to brachycephalic upper airway crisis.

    Affected Organ Systems

    Although the body has effective mechanisms to defend cells from thermal injury, there is an individual point for each patient at which the body can no longer compensate and severe heatstroke ensues. Injury to multiple organ systems can be seen in cases of heatstroke. Organ systems commonly affected are the gastrointestinal tract and the coagulation, renal, cardiac, pulmonary, and central nervous systems.

    Exposure to extreme temperatures that cause direct tissue damage is called direct cytotoxicity.4 The result of direct cytotoxicity varies with tissue type and depends on the tissue’s critical thermal maximum. The critical thermal maximum attempts to quantify the level and duration of heat necessary to initiate tissue injury.3 At extreme body temperatures of 120.2° to 122°F (49° to 50°C), necrosis destroys all cellular structures in less than 5 minutes.3,21 As the body continues to be exposed to high temperatures, additional proinflammatory cytokines are produced, perpetuating the inflammatory state and cellular injury. These cytokines are markers of SIRS and, if allowed to persist, contribute to the development of multiple organ failure.

    Gastrointestinal Tract

    Damage to the gastrointestinal tract is caused in part by direct cytotoxicity and in part by prolonged splanchnic vasoconstriction and hypoperfusion, which happen early during the compensatory stages of heatstroke.3 In animal models of heat stress, prolonged periods of splanchnic vasoconstriction and hypoperfusion lead to intestinal and hepatocellular hypoxia.3 Hypoxia causes the generation of highly reactive oxygen and nitrogen species that accelerate mucosal injury and results in hyperpermeability of the intestinal mucosa.3 Increased mucosal permeability predisposes the patient to gastrointestinal bacterial translocation, mainly of resident gram-negative bacterial endotoxin.22 In experimental studies of heat stress in veterinary species, radiolabeled endotoxin was not only identified in systemic circulation, but also increased with increasing body temperature.3,23,24 The resultant endotoxemia and bacteremia perpetuate the acute phase response and increase production of inflammatory cytokines, contributing to cardiovascular instability and the development of sepsis. Septic shock can result as TNF-α and IL-6 induce endothelial cell activation and the release of endothelial vasoactive factors, such as nitric oxide and endothelins, leading to hypotension.3,23–26

    Coagulation System      

    Direct cytotoxicity results in endothelial damage, marked by an increase in plasma markers of endothelial activation: von Willebrand factor antigen, intracellular adhesion molecule-1, and endothelin.27 Subsequent platelet and leukocyte adherence to areas of endothelial damage further contributes to the proinflammatory state.8 Endothelial damage activates the coagulation cascade in the early stages of heatstroke through the release of thromboplastin and factor XII.27,28 Procoagulation predominates because levels of thrombin–antithrombin III complexes and soluble fibrin monomers increase while levels of anticoagulation factors, such as protein C, protein S, and antithrombin III, decrease.3,8 The fibrinolytic pathway is activated by increased levels of plasmin-antiplasmin complexes and D-dimers and decreased concentrations of plasminogen, predisposing heatstroke patients to developing disseminated intravascular coagulation (DIC).19,27,29 The incidence of DIC was confirmed in >48% of cases in two recent canine studies involving heatstroke.19,30

    Renal System

    Acute kidney injury was noted in 33% of canine heatstroke patients.19 In heatstroke patients, acute kidney injury results from direct cytotoxicity, ischemic injury from vasoconstriction during initial compensatory phases, hypovolemia, and vascular insults.8,22,29,31 Histologic evaluation of kidneys from canine heatstroke patients suggests that these mechanisms of injury lead to moderate to severe interstitial and glomerular congestion, interstitial hemorrhage, and mild to severe tubular degeneration with necrosis.30 Further renal injury can develop from excess myoglobin filtration secondary to massive rhabdomyolysis.8,29

    Cardiovascular System

    Initially, the cardiovascular system is vital to the body’s thermoregulatory process as cardiac output, peripheral vasodilation, and central vasoconstriction increase. As the disease process progresses, these compensatory mechanisms fail, and distributive shock results from the decreased systemic vascular resistance caused by central vasodilation and venous pooling. Cardiac myocytes are susceptible to direct cytotoxicity, resulting in fragmentation of the myocardium and loss of myofibrillar striations.8,32 These structural changes lead to myocardial conduction defects and ventricular arrhythmias.8 Histologic evaluation of hearts from canine heatstroke patients showed the presence of epicardial, endocardial, and myocardial hemorrhage.30

    Pulmonary System

    The pulmonary system can suffer from direct cytotoxicity. Direct thermal injury to the pulmonary endothelium results in vasculitis and may progress to acute lung injury or acute respiratory distress syndrome (ARDS). Histologic evaluation of lungs from canine heatstroke patients revealed that all dogs had mild to severe diffuse pulmonary edema and hyperemia.30 ARDS was a common finding in one human heatstroke study.33 These changes impair respiratory function and further decrease heat dissipation, contributing to the exacerbation of hyperthermia.

    Central Nervous System

    The central nervous system is extremely sensitive to hyperthermia. Direct cytotoxicity causes neuronal injury and cell death.8 Cerebral edema, hemorrhage, and mild to moderate neuronal necrosis were noted on necropsy in canine heatstroke patients.30 Dopamine, serotonin, and many of the proinflammatory cytokines (IL-1, TNF-α, and IL-6) that are elevated during heatstroke are thought to be mediators for cerebral edema and decreases in cerebral perfusion.34 These underlying cerebral changes are responsible for the neurologic derangements that many heatstroke patients develop.

    Summary

    The body relies on thermoregulation to maintain a core body temperature that preserves normal cellular function. This process involves an intricate balance between heat dissipation and conservation. Thermoregulation is achieved through evaporation, radiation, convection, and conduction. Temperature changes are sensed by thermoreceptors and appropriate compensatory processes are initiated, including the acute phase response and activation of heat shock proteins. If heat stress is left unchecked, protective mechanisms fail, leading to organ injury. Cellular structures can be damaged through acute cardiovascular changes or direct cytotoxicity. As organ systems are injured, a chain reaction is started, leading to further damage. Organ systems commonly affected in heatstroke patients include the gastrointestinal tract and the coagulation, renal, cardiovascular, pulmonary, and central nervous systems.

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    References

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