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Heat Stroke

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ABSTRACT

Heat stroke is a life‐threatening condition clinically diagnosed as a severe elevation in body temperature with central nervous system dysfunction that often includes combativeness, delirium, seizures, and coma. Classic heat stroke primarily occurs in immunocompromised individuals during annual heat waves. Exertional heat stroke is observed in young fit individuals performing strenuous physical activity in hot or temperature environments. Long‐term consequences of heat stroke are thought to be due to a systemic inflammatory response syndrome. This article provides a comprehensive review of recent advances in the identification of risk factors that predispose to heat stroke, the role of endotoxin and cytokines in mediation of multi‐organ damage, the incidence of hypothermia and fever during heat stroke recovery, clinical biomarkers of organ damage severity, and protective cooling strategies. Risk factors include environmental factors, medications, drug use, compromised health status, and genetic conditions. The role of endotoxin and cytokines is discussed in the framework of research conducted over 30 years ago that requires reassessment to more clearly identify the role of these factors in the systemic inflammatory response syndrome. We challenge the notion that hypothalamic damage is responsible for thermoregulatory disturbances during heat stroke recovery and highlight recent advances in our understanding of the regulated nature of these responses. The need for more sensitive clinical biomarkers of organ damage is examined. Conventional and emerging cooling methods are discussed with reference to protection against peripheral organ damage and selective brain cooling. Published 2015. Compr Physiol 5:611‐647, 2015.

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Figure 1. Figure 1. Schematic of the sequence of events occurring in response to heat stroke that stimulate a systemic inflammatory response syndrome that leads to multi‐organ dysfunction and death.
Figure 2. Figure 2. Theoretical concept of unregulated and regulated changes in core temperature (Tc) with reference to the temperature set point (Tset). (A) Hyperthermia represents an increase in Tc in the absence of a change in Tset. In response to climatic heat stress, exercise or the combination of these factors, heat gain (HG), and/or heat production (HP) exceed heat loss (HL) and Tc rises above Tset as the organism becomes hyperthermic. Following removal from the heat, cooling or cessation of exercise, HL exceeds HG/HP and Tc returns to baseline. (B) Fever is defined as a regulated increase in body temperature that is actively established and defended by behavioral and autonomic thermoeffector responses. An increase in heat conservation (HC) and/or HG and decrease in HL stimulate a rise in Tc to a new elevated level. The rising phase of fever is associated with shivering (increases HP), the use of blankets (increase HC) until a new elevated level of Tc is attained. Note that while fever is maintained, Tc oscillates around Tset and the individual is considered normothermic with HP=HL. Once fever breaks, HL exceeds HC/HP as the individual sweats, removes clothing, etc. to return Tc to the baseline level. Reprinted, with permission, from ().
Figure 3. Figure 3. Idiosyncratic hyperthermia during mild, low‐intensity exercise in a hot environment. Higher rectal temperature during exercise‐heat stress on day 3 was associated with cellulitis. Reprinted, with permission, from ().
Figure 4. Figure 4. Hematoxylin and eosin (H&E) of multiple organ damage in heat stroke and control baboons. (A) H & E. Controls, no abnormalities (A, D, G, J, and M). Severe heat stroke baboons (B, E, H, K, and N) display vascular congestion and/or hemorrhage (straight arrows), thrombi (arrow‐heads), increased inflammatory cells (dashed arrows), and disruption of architecture (asterisks). Moderate heat stroke shows similar changes but less severe (C, F, I, L, and O). Reprinted with permission, from (306).
Figure 5. Figure 5. Cerebellar atrophy is a common heat stroke response shown by computer tomography (CT) scan. A 45‐year‐old man was unconscious and hyperthermic with convulsions at the time of hospital admission. (A) Cerebellum appeared normal 2 weeks following collapse, but showed progressive atrophy from 10 weeks (B) to 11 weeks (C) of recovery. Hypothalamic damage was not reported in this patient. With, kind permission, from Springer Science and Business Media ().
Figure 6. Figure 6. Mice display ∼1°C fever the day following heat stroke that is not attenuated by prior treatment with the nonsteroidal anti‐inflammatory drug, indomethacin. Responses compared to mice that received no drug or indomethacin in the absence of heat stroke. Indomethacin had no effect on normal (resting) core temperature. (A) Circadian core temperature responses; (B) 12‐h average daytime responses. Reprinted, with permission, from ().
Figure 7. Figure 7. Firing rate responses of two warm‐sensitive neurons in a preoptic hypothalamic tissue slice. Each record shows spontaneous firing rate (impulses/s) and tissue slice temperature (°C) with thermal coefficient expressed as imp·s−1·°C−1 (A) Decreased firing rate of a warm‐sensitive neuron during hypercapnia and isocapnic acidosis. (B) Decreased firing rate of a warm‐sensitive neuron to two hypercapnic exposures with no response during isohydric hypercapnia. Reprinted, with permission, from ().
Figure 8. Figure 8. Mechanisms implicated in the pathophysiological responses to heat stroke that often culminate in multi‐organ damage and failure. Hyperthermia causes a reduction in cerebral blood flow that may be the initiating stimulus for increased blood brain barrier permeability and brain injury. Hypothalamic damage has been thought to mediate hypothermia and/or recurrent hyperthermia during heat stroke recovery, although there are no clinical or experimental data to support this hypothesis. Skin blood flow is increased during heat exposure to facilitate heat loss to the environment and limit hyperthermia. This response is supported by a decrease in gut blood flow that facilitates redistribution of blood to the skin surface. Gut ischemia causes the gut to become “leaky,” which facilitates passage of endotoxin into the systemic circulation. Cytokines, chemokines, and other inflammatory mediators are thought to be initiated by immune responses to endotoxin. Thermal injury to the vascular endothelium and initiation of coagulation/fibrinolysis pathways leads to arteriole and capillary occlusion (microvascular thrombosis) or excessive bleeding (consumptive coagulation). Gray shading represents hypothetical mechanisms of injury. Reprinted with permission, from (216).
Figure 9. Figure 9. Hematoxylin and eosin stain of tissue sections in control and heat stressed study groups. BRAIN: (A) Normal pallidum in sham‐heated controls; (B) early neuronal necrosis (arrows) in scattered neurons. Normal neurons (white arrowheads) in moderate heat stroke; (C) widespread neuronal necrosis (arrows) in severe heatstroke; (D) normal cerebellum: normal Purkinje cells (white arrowheads) in sham‐heated controls; (E) early Purkinje cells necrosis (solid arrows) and normal Purkinje cells (white arrowheads) in moderate heat stroke. Reprinted, with permission, from ().
Figure 10. Figure 10. Transmission electron micrographs of small intestinal epithelial cells of heat stroked rats. Partial photograph of adjacent enterocytes showing damage to the microvilli of heat stroke rats compared to controls. Reprinted, with permission, from ().


Figure 1. Schematic of the sequence of events occurring in response to heat stroke that stimulate a systemic inflammatory response syndrome that leads to multi‐organ dysfunction and death.


Figure 2. Theoretical concept of unregulated and regulated changes in core temperature (Tc) with reference to the temperature set point (Tset). (A) Hyperthermia represents an increase in Tc in the absence of a change in Tset. In response to climatic heat stress, exercise or the combination of these factors, heat gain (HG), and/or heat production (HP) exceed heat loss (HL) and Tc rises above Tset as the organism becomes hyperthermic. Following removal from the heat, cooling or cessation of exercise, HL exceeds HG/HP and Tc returns to baseline. (B) Fever is defined as a regulated increase in body temperature that is actively established and defended by behavioral and autonomic thermoeffector responses. An increase in heat conservation (HC) and/or HG and decrease in HL stimulate a rise in Tc to a new elevated level. The rising phase of fever is associated with shivering (increases HP), the use of blankets (increase HC) until a new elevated level of Tc is attained. Note that while fever is maintained, Tc oscillates around Tset and the individual is considered normothermic with HP=HL. Once fever breaks, HL exceeds HC/HP as the individual sweats, removes clothing, etc. to return Tc to the baseline level. Reprinted, with permission, from ().


Figure 3. Idiosyncratic hyperthermia during mild, low‐intensity exercise in a hot environment. Higher rectal temperature during exercise‐heat stress on day 3 was associated with cellulitis. Reprinted, with permission, from ().


Figure 4. Hematoxylin and eosin (H&E) of multiple organ damage in heat stroke and control baboons. (A) H & E. Controls, no abnormalities (A, D, G, J, and M). Severe heat stroke baboons (B, E, H, K, and N) display vascular congestion and/or hemorrhage (straight arrows), thrombi (arrow‐heads), increased inflammatory cells (dashed arrows), and disruption of architecture (asterisks). Moderate heat stroke shows similar changes but less severe (C, F, I, L, and O). Reprinted with permission, from (306).


Figure 5. Cerebellar atrophy is a common heat stroke response shown by computer tomography (CT) scan. A 45‐year‐old man was unconscious and hyperthermic with convulsions at the time of hospital admission. (A) Cerebellum appeared normal 2 weeks following collapse, but showed progressive atrophy from 10 weeks (B) to 11 weeks (C) of recovery. Hypothalamic damage was not reported in this patient. With, kind permission, from Springer Science and Business Media ().


Figure 6. Mice display ∼1°C fever the day following heat stroke that is not attenuated by prior treatment with the nonsteroidal anti‐inflammatory drug, indomethacin. Responses compared to mice that received no drug or indomethacin in the absence of heat stroke. Indomethacin had no effect on normal (resting) core temperature. (A) Circadian core temperature responses; (B) 12‐h average daytime responses. Reprinted, with permission, from ().


Figure 7. Firing rate responses of two warm‐sensitive neurons in a preoptic hypothalamic tissue slice. Each record shows spontaneous firing rate (impulses/s) and tissue slice temperature (°C) with thermal coefficient expressed as imp·s−1·°C−1 (A) Decreased firing rate of a warm‐sensitive neuron during hypercapnia and isocapnic acidosis. (B) Decreased firing rate of a warm‐sensitive neuron to two hypercapnic exposures with no response during isohydric hypercapnia. Reprinted, with permission, from ().


Figure 8. Mechanisms implicated in the pathophysiological responses to heat stroke that often culminate in multi‐organ damage and failure. Hyperthermia causes a reduction in cerebral blood flow that may be the initiating stimulus for increased blood brain barrier permeability and brain injury. Hypothalamic damage has been thought to mediate hypothermia and/or recurrent hyperthermia during heat stroke recovery, although there are no clinical or experimental data to support this hypothesis. Skin blood flow is increased during heat exposure to facilitate heat loss to the environment and limit hyperthermia. This response is supported by a decrease in gut blood flow that facilitates redistribution of blood to the skin surface. Gut ischemia causes the gut to become “leaky,” which facilitates passage of endotoxin into the systemic circulation. Cytokines, chemokines, and other inflammatory mediators are thought to be initiated by immune responses to endotoxin. Thermal injury to the vascular endothelium and initiation of coagulation/fibrinolysis pathways leads to arteriole and capillary occlusion (microvascular thrombosis) or excessive bleeding (consumptive coagulation). Gray shading represents hypothetical mechanisms of injury. Reprinted with permission, from (216).


Figure 9. Hematoxylin and eosin stain of tissue sections in control and heat stressed study groups. BRAIN: (A) Normal pallidum in sham‐heated controls; (B) early neuronal necrosis (arrows) in scattered neurons. Normal neurons (white arrowheads) in moderate heat stroke; (C) widespread neuronal necrosis (arrows) in severe heatstroke; (D) normal cerebellum: normal Purkinje cells (white arrowheads) in sham‐heated controls; (E) early Purkinje cells necrosis (solid arrows) and normal Purkinje cells (white arrowheads) in moderate heat stroke. Reprinted, with permission, from ().


Figure 10. Transmission electron micrographs of small intestinal epithelial cells of heat stroked rats. Partial photograph of adjacent enterocytes showing damage to the microvilli of heat stroke rats compared to controls. Reprinted, with permission, from ().
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Lisa R. Leon, Abderrezak Bouchama. Heat Stroke. Compr Physiol 2015, 5: 611-647. doi: 10.1002/cphy.c140017