Pathophysiology Of Heat Stroke Research Articles

Neurological disorders with general overheating of the body (scientific and literary review)

Based on the understanding of the pathophysiology of heat stroke, it has been suggested that heat stroke can be considered as a form of hyperthermia that is associated with a systemic inflammatory response leading to a syndrome of multiple organ dysfunction in which encephalopathy predominates. Mechanisms of neuronal injury in heat stroke include: cellular effects (damage to membranes, mitochondria, and DNA, stimulation of excitotoxic mechanisms, protein denaturation), local effects (ischemia, inflammatory changes, edema, cytokine release, vascular damage), systemic effects (changes in cerebral blood flow, endotoxemia, translocation of bacteria through a dysfunctional gastrointestinal tract). Neurological manifestations of heat stroke develop in 3 stages according to the time of occurrence: acute, convalescent and late. In the acute stage, cerebral dysfunction prevails. Overheating of the body directly caused polyetiological cerebral dysfunction with deep suppression of consciousness in the acute stage; circulatory shock, hypoxia and cerebral ischemia, excessive accumulation of cytotoxic free radicals and oxidant brain damage developed. During the convalescence stage, cerebral dysfunction gradually decreases. This stage is characterized by transient cerebellar dysfunction. For the late stage, long-term neurological and cardiovascular complications with a constant risk of death are typical. When late stage with permanent neurologic deficits develop, cerebellar dysfunction is the most common symptom. The delayed onset of degeneration and deafferentation suggests that the syndrome is not caused by the primary lesion itself but may be a consequence of postsynaptic hypersensitivity or secondary reorganization of the involved pathways.

Insights into pathophysiology and therapeutic strategies for heat stroke: Lessons from a baboon model.

Heat stroke is a perilous condition marked by severe hyperthermia and extensive multiorgan dysfunction, posing a considerable risk of mortality if not promptly identified and treated. Furthermore, the complex biological mechanisms underlying heat stroke-induced tissue and cell damage across organ systems remain incompletely understood. This knowledge gap has hindered the advancement of effective preventive and therapeutic strategies against this condition. In this narrative review, we synthesize key insights gained over a decade using a translational baboon model of heat stroke. By replicating heat stroke pathology in a non-human primate species that closely resembles humans, we have unveiled novel insights into the pathways of organ injury and cell death elicited by this condition. Here, we contextualize and integrate the lessons learned concerning heat stroke pathophysiology and recovery, areas that are inherently challenging to investigate directly in human subjects. We suggest novel research directions to advance the understanding of the complex mechanisms underlying cell death and organ injury. This may lead to precise therapeutic strategies that benefit individuals suffering from this debilitating condition.

Lack of lymphocytes exacerbate heat stroke severity in male mice through enhanced inflammatory response

Though it has long been thought that the immune system is implicated in the pathophysiology of heat stroke, the underlying mechanisms are still poorly understood. As it has been reported in the literature that lymphocyte disturbance occurs in heat stroke patients or animals, we attempted to seek experimental evidence to define the role of lymphocytes in the pathophysiology of heat stroke. In our study, we used male Balb/c mice to establish a passive heat stroke model. We found that lymphocyte-deficient Severe combined immunodeficient (SCID) mice exposed to heat stress exhibited exacerbated heat stroke severity, which could be indicated by increased rates of mortality and serum levels of inflammatory cytokines compared to wildtype control mice. We further showed, through the depletion of T lymphocytes in wildtype mice and the transfer of wildtype lymphocytes into SCID mice, respectively, that T lymphocytes were both necessary and sufficient to alleviate the severity of heat stroke by inhibiting the early inflammatory response. Moreover, we found that the severity of heat injuries in heat-stressed wildtype mice showed great inter-individual variability, and the early number of T lymphocytes could be negatively associated with the severity of heat stroke. Our results suggest that lack of T lymphocytes could exacerbate the severity of heat stroke by augmenting inflammatory response, and the early circulating T lymphocytes may serve as a potential biomarker for the diagnosis of heat stroke.

The Role of Skeletal Muscles in Exertional Heat Stroke Pathophysiology

The active participation of skeletal muscles is a unique characteristic of exertional heat stroke. Nevertheless, the only well-documented link between skeletal muscle activities and exertional heat stroke pathophysiology is the extensive muscle damage (e. g., rhabdomyolysis) and subsequent leakage of intramuscular content into the circulation of exertional heat stroke victims. Here, we will present and discuss rarely explored roles of skeletal muscles in the context of exertional heat stroke pathophysiology and recovery. This includes an overview of heat production that contributes to severe hyperthermia and the synthesis and secretion of bioactive molecules, such as cytokines, chemokines and acute phase proteins. These molecules can alter the overall inflammatory status from pro- to anti-inflammatory, affecting other organ systems and influencing recovery. The activation of innate immunity can determine whether a victim is ready to return to physical activity or experiences a prolonged convalescence. We also provide a brief discussion on whether heat acclimation can shift skeletal muscle secretory phenotype to prevent or aid recovery from exertional heat stroke. We conclude that skeletal muscles should be considered as a key organ system in exertional heat stroke pathophysiology.

Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke.

Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed.

Intestinal Injury in Heat Stroke.

Heat stroke is a life-threatening syndrome that is characterized by its severe clinical symptoms, rapid progression, and high rate of mortality. Recently, research has indicated that a dysfunctional intestinal epithelia barrier plays an important role in the pathophysiology of heat stroke. Protecting the intestines from heat stress had been identified as a potentially effective treatment for patients with heat stroke and may reduce the innate immune response caused by endotoxins in circulation. The aim of this review is to discuss this key event in heat stroke and to describe the mechanism during progression. Direct injuries and secondary impairments of the intestine induced by heat stress are discussed; recent studies that refer to intestine-specific prevention and treatment in heat stroke and heat stress-induced injuries are also summarized. A more detailed pathogenesis of heat stroke needs to be elucidated so that potentially effective means of treatment and prevention of heat stroke can be developed and studied.

Pyroptosis of HUVECs can be induced by heat stroke

Heat stroke is a serious pathological condition with high mortality. Vascular endothelial cell injury is a key feature in the pathogenesis of heat stroke, but the specific pathophysiological process whereby this occurs is still unclear. Currently, relevant studies are primarily based upon examination of apoptosis. Recently, pyroptosis, a new form of inflammation-related programmed cell death, was also demonstrated to be involved in heat stroke pathophysiology. Herein, we present evidence that vascular endothelial cell pyroptosis can be induced by heat stress in a time- and temperature-dependent manner. Furthermore, this process can be significantly inhibited by GSDMD siRNA. These findings suggest a new therapeutic target for heat stroke.

Systemic Inflammation Mediates the Effects of Endotoxemia in the Mechanisms of Heat Stroke

Heat stroke is triggered by heat, but is driven by endotoxemia and the downstream effects of systemic inflammation, acute phase response and the pyrogenic response. Whereas heat stroke and its related fatality commonly occur at core temperature (Tc) >40°C, healthy individuals have tolerated Tc 40°C-42°C without symptoms of heat stroke, suggesting that besides hyperthermia, there are other factors that can also cause heat stroke. The “Dual-pathway model (DPM)” suggests that heat stroke is triggered by the endotoxemia pathway at Tc up to ~ 42°C and independently, by heat toxicity at Tc >42°C. The second pathway in the DPM is based on evidence showing that cytoskeletal structures start to disintegrate at ambient temperature >41.5°C. Since most exertional stroke cases occur at Tc <42°C, the endotoxemia pathway, and not heat, might be the primary cause of heat stroke in the active population. Current evidence suggests that exercising under a poor state of health and a compromised immune system may also cause heat stroke, independent from the effects of hyperthermia. Strategies to prevent heat stroke should put equal emphasis on maintaining a good state of health and immune function. The current practice of focusing primarily on heat strain and hydration to prevent heat stroke may not have comprehensively addressed the pathophysiology of heat stroke and may explain why heat stroke continues to occur after more than 2000 years.

Heat Stroke Pathophysiology

G-12 Highlighted Symposium - Heat Tolerance Test: Relevance for Return to Duty, Return to Play Saturday, June 4, 2016, 9: 00 AM - 11: 00 AM Room: 304: PDF Only

Physical Effort Affects Heatstroke Thermoregulatory Response and Mortality in Rats.

Animals suffering from heatstroke (HS) after physical effort may have different heat-related core temperature (Tc) responses compared with passive HS. In the present study, conscious and unrestrained rats were exposed to ambient temperature (Ta) of 39.5°C ± 0.2°C with or without running (run-heated or rest-heated, respectively) until HS onset, which was defined as the systolic blood pressure starting to drop. In comparison with rest-heated rats, run-heated rats had a significantly shorter latency of HS onset. Physical effort did not have significant influence on hyperthermia severity (43.3°C ± 0.2°C at rest-heated, and 43.4°C ± 0.2°C at run-heated), but it could significantly decrease the thermal load to develop HS (315.1°C ± 37.3°C·min for rest-heated, and 133.5 ± 21.4 °C·min for run-heated). Working component during heat exposure may contribute to a decreased survival rate of HS (46.9% at rest-heated and 31.3% at run-heated). Impaired heat dissipation during recovery may be responsible for relative poor survival of run-heated rats. In both groups, survival was affected by Tc at HS onset and thermal area. Hypothermia (Tc <35°C) developed after HS onset, with no significant difference in Tc,min between the rest-heated and run-heated groups. These thermoregulatory responses to HS after physical effort may provide insight into HS pathophysiology.

Pathophysiology of Heat Stroke

Pathophysiology of Heat Stroke

Eicosapentaenoic Acid Enhances Heat Stress-Impaired Intestinal Epithelial Barrier Function in Caco-2 Cells

ObjectiveDysfunction of the intestinal epithelial tight junction (TJ) barrier is known to have an important etiologic role in the pathophysiology of heat stroke. N-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a role in maintaining and protecting the TJ structure and function. This study is aimed at investigating whether n-3 PUFAs could alleviate heat stress-induced dysfunction of intestinal tight junction.MethodsHuman intestinal epithelial Caco-2 cells were pre-incubated with EPA, DHA or arachidonic acid (AA) and then exposed to heat stress. Transepithelial electrical resistance (TEER) and Horseradish Peroxidase (HRP) permeability were measured to analyze barrier integrity. Levels of TJ proteins, including occludin, ZO-1 and claudin-2, were analyzed by Western blot and localized by immunofluorescence microscopy. Messenger RNA levels were determined by quantitative real time polymerase chain reaction (Q-PCR). TJ morphology was observed by transmission electron microscopy.ResultsEPA effectively attenuated the decrease in TEER and impairment of intestinal permeability in HRP flux induced by heat exposure. EPA significantly elevated the expression of occludin and ZO-1, while DHA was less effective and AA was not at all effective. The distortion and redistribution of TJ proteins, and disruption of morphology were also effectively prevented by pretreatment with EPA.ConclusionThis study indicates for the first time that EPA is more potent than DHA in protecting against heat-induced permeability dysfunction and epithelial barrier damage of tight junction.

Cytokines and their role in hyperthermia and heat stroke

Cytokines are intracellular peptides that serve as immune mediators. The levels of both pro- and anti-inflammatory cytokines have been demonstrated to rise in the event of heat stroke in both human and animal models. Different hyperthermic states, including both normal exercise-induced hyperthermia and classical and exertional heat stroke, result in unique characteristic profiles of plasma cytokines. The complexity of the interaction between pro- and anti-inflammatory cytokines is outlined in the vast number of experimental studies and clinical observations reported in the literature. However, there is no unanimous logic in studying the changes in cytokine levels, and therefore, it is difficult to compare the effects seen in the different reports. The strong inflammatory response to heat stroke increases after the cessation of heat stress and is intricately involved both in damage-generating processes and in repair mechanisms that are put into action during the recovery phase. In surviving individuals, this response diminishes in magnitude as time progresses and eventually subsides to allow return-to-normal homeostasis. A greater magnitude of the inflammatory response is often associated with poor prognosis and even fatalities, suggesting an imbalance of the immune system, which causes an unregulated inflammatory response. This review describes the common known processes relating to the predominant cytokines altered in the event of heat injury. The role of cytokines, specifically in the pathophysiology of heat stroke, is elaborated and depicted as part of a biaxial model pertaining to the physiological and cellular/biochemical aspects of heat stroke.

213

Introduction: Increased levels of circulating endotoxin have been identified in patients with heatstroke; however, the exact mechanisms of heatstroke are not fully elucidated. We questioned whether susceptibility to the circulating endotoxin is increased in pathogenesis of heatstroke. Hypothesis: We hypothesized that exposure to heat environment increases susceptibility to lipopolysaccharide (LPS) in mice. Methods: Male 8- to 10- week-old C3H/HeN mice were divided into two groups (n = 25/group). The animals were anesthetized and placed in heat environment (42 degrees C) or in normal environment (23 degrees C) for one hour. Then, mice were injected intraperitonially with 50, 100, 200, 400 or 800 mcg of LPS (n = 5/subgroup). All mice were housed at normal ambient temperature (23 degrees C) after injection. Mortality was recorded for up to 5 days after heat exposure and the lethal dose (LD50) of LPS was determined in each group. We then measured changes of serum cytokine levels after LPS injection. After one hour exposure to heat (42 degrees C), LPS (141 mcg/body) was injected intraperitonially (H group). Control group (C group) was given the same doses of LPS without heat stress (23 degrees C). Blood samples were taken at 1, 2, 6, 12 hours after injection for determination of TNF-alpha levels, at 2, 6, 12, 24, 36, 48 hours for IL-6 levels and at 2, 6, 12, 24 hours for IL-10 levels. Results: Groups of mice injected 200 mcg or 400 mcg of LPS after heat stress showed significantly higher mortality compared to the control group. LD50 of LPS was determined 141 mcg in the heat exposed group, whereas 258 mcg in the control group. TNF-alpha level of H group was significantly higher than that of C group at 1 and 2 hours after LPS injection. IL-6 levels rapidly elevated after LPS injection in both groups. Elevated IL-6 level was sustained 24 h and 36 h after LPS injection in H group whereas IL-6 level declined earlier in C group. Difference of serum IL-10 levels between C group and H group was not statistically significant. Conclusions: These data demonstrate that increased susceptibility is related to mortality of heatstroke and enhanced cytokine production plays an important role in the pathophysiology of heatstroke.

Tissue and circulating expression of IL-1 family members following heat stroke

Interleukin-1 (IL-1) is thought to have a significant role in the pathophysiology of heat stroke (HS), although little is known regarding the actions or expression patterns of the IL-1 family. This study tested the hypotheses that following HS IL-1 family gene expression is dynamic, while loss of IL-1 signaling enhances recovery. IL-1 family expression was determined in plasma, spleen, and liver from C57BL/6J mice (n=24 control, n=20 HS) at maximum core temperature (Tc,Max), hypothermia, and 24 h post-HS (24 h). Soluble IL-1 receptor subtype I (sIL-1RI) protein expression peaked at 24 h (14,659.01±2,016.28 pg/ml, P<0.05), while sIL-1RII peaked at hypothermia (19,099.30±1,177.07 pg/ml). IL-1α gene expression in the spleen (ninefold) and liver (fourfold) along with IL-1RI (threefold spleen and fivefold liver) were maximal at hypothermia. Spleen IL-1β gene expression peaked at Tc,Max (fourfold) but at hypothermia (fourfold) in liver. Gene expression of the IL-1 family member IL-18 peaked (2.5-fold) at Tc,Max but was similar at all other time points. Subsequent studies revealed that despite accruing a greater heating area (298±16 vs. 247±13°C·min, P<0.05), IL-1RI knockout (KO) mice (n=14) showed an attenuated hypothermia depth (28.5±0.2 vs. 27.3±0.5°C, P<0.05) and duration (675±82 vs. 1,283±390 min, P<0.05) with a higher 24 h Tc (36.9 vs. 34.1°C, P<0.05) compared with C57BL/6J mice (n=8). The current results demonstrate that following HS IL-1 family gene expression is altered and IL-1RI KO mice display Tc responses consistent with a more rapid recovery.

Bacterial translocation in heat stroke

The scientific community is fully aware of the importance of heat-related illness and heat stroke syndrome. Numerous guidelines have been recently published and most of them agree on the key role played by the intestine. Likewise, the role of endotoxinemia in the pathophysiology is well established. However, the possibility of bacterial translocation is not mentioned. Our patient illustrates the likelihood of bacterial translocation in heat stroke and consistently the potential need of antibiotic therapy. A 45-year-old man diagnosed with paranoid schizophrenia was confined in a penitentiary center. One summer day in which a temperature of 41 degrees C was observed in the shade, the patient was found in deep coma with an axillary temperature of 42 degrees C. Multiorgan failure was detected in the hospital. Other causes of coma and/or hyperthermia were excluded, and heat stroke was diagnosed. Blood cultures were positive for Pseudomonas aeruginosa and Escherichia coli. Infection site was not identified despite of an exhaustive search. The patient fully recovered after 48 hours. On the basis of review of the literature, we think that bacterial translocation can take part in the pathophysiology of heat stroke. Therefore, antibiotic treatment must be evaluated in heat stroke patients.

A Conscious Mouse Model that Delineates the Role of Cytokines in Heat Stroke Pathophysiology

A Conscious Mouse Model that Delineates the Role of Cytokines in Heat Stroke Pathophysiology

Human body temperature regulation in extremely stressful environment: epidemiology and pathophysiology of heat stroke

Biological functions are basically dependent on the thermosensitive characteristics of the proteins and fatty substances composing the body structure. In a stressful environment, the extremely high human body temperatures detected by computer screening in our laboratory of exercise physiology are in the range of 41.0–46.5 °C, of which the highest temperature was identical with the highest value described in the latest Guinness Book of Records. The highest body temperature value of 46.5 °C reported in (Solvis et al. Ann. Emerg. Med. 11(5) (1982) 269) is thought to be extremely high compared to those of the other vertebrates. The concept of critical thermal maximum (CTM) has been defined in the present literature as the minimal degree of long-term hyperthermia, beyond which life-threatening damage develops in a homeotherm. In man the CTM has been estimated at 41.6–42.0 °C. Therefore, in the present paper, physiological, pathological and clinical cases of hyperthermia beyond 42.0 °C, as detected in 51 papers, and the biological inhibitory mechanisms preventing hyperthermia in an extremely high ambient temperature and the immunological protection mechanisms associated with strong heat stresses, were discussed from the viewpoints of the secondary chemical regulation as well as of the negative feed back system that controls body temperature.

Heat stress induces a biphasic thermoregulatory response in mice.

Previous animal models of heat stress have been compromised by methodologies, such as restraint and anesthesia, that have confounded our understanding of the core temperature (T(c)) responses elicited by heat stress. Using biotelemetry, we developed a heat stress model to examine T(c) responses in conscious, unrestrained C57BL/6J male mice. Before heat stress, mice were acclimated for >4 wk to an ambient temperature (T(a)) of 25 degrees C. Mice were exposed to T(a) of 39.5 +/- 0.2 degrees C, in the absence of food and water, until they reached maximum T(c) of 42.4 (n = 11), 42.7 (n = 12), or 43.0 degrees C (n = 11), defined as mild, moderate, and extreme heat stress, respectively. Heat stress induced an approximately 13% body weight loss that did not differ by final group T(c); however, survival rate was affected by final T(c) (100% at 42.4 degrees C, 92% at 42.7 degrees C, and 46% at 43 degrees C). Hypothermia (T(c) < 34.5 degrees C) developed after heat stress, with the depth and duration of hypothermia significantly enhanced in the moderate and extreme compared with the mild group. Regardless of heat stress severity, every mouse that transitioned out of hypothermia (survivors only) developed a virtually identical elevation in T(c) the next day, but not night, compared with nonheated controls. To test the effect of the recovery T(a), a group of mice (n = 5) were acclimated for >4 wk and recovered at T(a) of 30 degrees C after moderate heat stress. Recovery at 30 degrees C resulted in 0% survival within approximately 2 h after cessation of heat stress. Using biotelemetry to monitor T(c) in the unrestrained mouse, we show that recovery from acute heat stress is associated with prolonged hypothermia followed by an elevation in daytime T(c) that is dependent on T(a). These thermoregulatory responses to heat stress are key biomarkers that may provide insight into heat stroke pathophysiology.

Medical Aspects of Harsh Environments

The Office of the Surgeon General of the United States Army has created a remarkable 2-volume set that comprehensively covers the essentials of medical care in extreme environments. Produced by the Borden Institute, the Army's medical publishing division, Medical Aspects of Harsh Environments, Vols 1–2, features contributions from noted authorities, clear photographs and figures, and a thorough list of references at the end of each chapter. Both volumes have been skillfully edited by US Army physicians Dave Ed Lounsbury and Ronald F. Bellamy, and detailed scientific information is presented in a highly readable format. Although the volumes are part of the Textbooks of Military Medicine series, they would make a welcome addition to any medical library. Volume 1 is divided into two sections: Hot Environments and Cold Environments. Hot Environments includes chapters on the physiology of exercise in hot climates, the pathophysiology of heatstroke, and the prevention of heat illness. The chapter on clinical diagnosis, management, and surveillance of exertional heat illness is particularly informative and includes an excellent review of the controversies related to the treatment of heatstroke. Cold Environments includes chapters on physiological responses to cold stress and hypothermia, prevention of cold injuries, cold water immersion, and the treatment of accidental hypothermia. Readers with an interest in research will appreciate the discussions of hypothermia studies from the military literature, many of which are not mentioned in other texts. Volume 2 begins with a section on mountain medicine, including acute mountain sickness and high-altitude cerebral edema, high-altitude pulmonary edema, and human adaptation to altitude. The chapter on high-altitude pulmonary edema is particularly well written, although the effects of beta-agonists such as salmeterol are not mentioned. The authors, however, cannot be faulted for this omission because major studies of beta-agonists and high-altitude pulmonary edema were almost certainly published after the chapter had already gone to press. This volume also reviews topics that are not typically found in most texts of emergency or wilderness medicine. For example, in addition to chapters on diving medicine, the reader will find chapters on shipboard medicine, motion sickness, acceleration effects on fighter pilots, biological and chemical warfare, medical support of special forces, and military spaceflight. A unique feature of the text is the integration of cases from prior military engagements, including those dating to ancient times. The historical perspective provided for mountain medicine, hypothermia related to shipwrecks, freezing cold injury, and other topics makes for fascinating reading and in no way detracts from the scientific merits of the work. On the contrary, these historical cases are used as effective teaching tools and add interest to the material presented. The work is timely, given recent military and political events. At the time of this writing, US and other forces have been deployed to Iraq and continue to be present in Afghanistan. Both of these countries are known for harsh environments with temperature extremes, and Afghanistan has difficult, mountainous terrain. With patient populations in such diverse climates and conditions, these volumes should be a valuable resource for military medical personnel. This work will also appeal to an audience much broader than the military medical community, and the reader will not find an excess of military jargon. Although some sections may be extraneous, civilian medical personnel who care for patients in extreme conditions will find these volumes to be of great clinical value. Furthermore, the merits of this work are not confined to clinical utility. Anyone with an interest in the physiological effects of extreme environments and patient care in the outdoors could enjoy and learn from this text. In summary, this is an outstanding work that contributes greatly to the medical literature. The foreword, written by the Surgeon General of the Army, James B. Peake, promises a third volume with a focus on prevention and further historical perspective. One wonders whether experiences from recent military action in the Middle East will provide additional insight for this coming volume—an insight that could contribute to the further advancement of patient care in harsh environments.