Severity Of Heatstroke Research Articles

The pathogenesis and therapeutic strategies of heat stroke-induced myocardial injury.

Heat stroke (HS) is a febrile illness characterized by an elevation in the core body temperature to over 40°C, accompanied by central nervous system impairment and subsequent multi-organ dysfunction syndrome. In recent years, the mortality rate from HS has been increasing as ambient temperatures continue to rise each year. The cardiovascular system plays an important role in the pathogenesis process of HS, as it functions as one of the key system for thermoregulation and its stability is associated with the severity of HS. Systemic inflammatory response and endothelial cell damage constitute pivotal attributes of HS, other factors such as ferroptosis, disturbances in myocardial metabolism and heat shock protein dysregulation are also involved in the damage to myocardial tissue in HS. In this review, a comprehensively detailed description of the pathogenesis of HS-induced myocardial injury is provided. The current treatment strategies and the promising therapeutic targets for HS are also discussed.

Holistic view of heat acclimation alleviated intestinal lesion in mice with heat stroke based on microbiome-metabolomics analysis.

The severity of heat stroke (HS) is associated with intestinal injury, which is generally considered an essential issue for HS. Heat acclimation (HA) is considered the best strategy to protect against HS. In addition, HA has a protective effect on intestinal injuries caused by HS. Considering the essential role of gut microbes in intestinal structure and function, we decided to investigate the potential protective mechanism of HA in reducing intestinal injury caused by HS. HA model was established by male C57BL/6J mice (5-6 weeks old, 17-19 g) were exposed at (34 ± 0.7)°C for 4 weeks to establish an animal HA model. The protective effect of HA on intestinal barrier injury in HS was investigated by 16S rRNA gene sequencing and nontargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics. According to the experimental results, HA can change the composition of the gut microbiota, which increases the proportion of lactobacilli, faecal bacteria, and urinobacteria but decreases the proportion of deoxycholic acid. Moreover, HA can reduce liver and kidney injury and systemic inflammation caused by HS and reduce intestinal injury by enhancing the integrity of the intestinal barrier. In addition, HA regulates inflammation by inhibiting NF-κB signalling and increasing tight junction protein expression in HS mice. HA induces changes in the gut microbiota, which may enhance tight junction protein expression, thereby reducing intestinal inflammation, promoting bile acid metabolism, and ultimately maintaining the integrity of the intestinal barrier. In conclusion, HA induced changes in the gut microbiota. Among the gut microbiota, lactobacilli may play a key role in the potential protective mechanism of HA.

A Systematic Review on Outcomes of Patients with Heatstroke and Heat Exhaustion.

Heatstroke (HS) is a severe form of heat-related illness (HRI) associated with high morbidity and mortality, representing a condition that includes long-term multiorgan dysfunction and susceptibility to further heat illness. In a systematic review searching Medline PubMed from the studies conducted between 2009 and 2020, 16 papers were identified. A hallmark symptom of heat stroke is CNS dysfunction (a hallmark sign of HS) which manifests as mental status changes, including agitation, delirium, epilepsy, or coma at the time of the collapse. Acute kidney injury (AKI), gut ischemia, blood clots in the stomach and small intestine, cytoplasmic protein clumps in the spleen, and injury of skeletal muscle (rhabdomyolysis) are all characteristics of peripheral tissue damage. Severe heat stroke tends to be complicated by rhabdomyolysis, especially in patients with exertional heat stroke. Rhabdomyolysis may lead to systemic effects, including the local occurrence of compartment syndrome, hyperkalemic cardiac arrest, and/or lethal disseminated intravascular coagulopathy. Untreated heat stroke might exacerbate psychosis, lactic acidosis, consumptive coagulopathy, hematuria, pulmonary edema, renal failure, and other metabolic abnormalities. Core body temperature and level of consciousness are the most significant indicators to diagnose the severity of heat stroke and prevent unfavorable consequences. Heatstroke is a life-threatening illness if not promptly recognized and effectively treated. This review highlighted that core body temperature and white blood cell count are significant contributing factors affecting heat stroke outcomes. Other factors contributing to the poor outcome include old age, low GCS, and prolonged hospital stay. The prevalence of both classic and exertional heatstroke can be reduced by certain simple preventive measures, such as avoiding strenuous activity in hot environments and reducing exposure to heat stress.

Factors in the Severity of Heat Stroke in China

When temperatures exceed 36�C and relative humidity passes 58%, citizens in China may experience heat stroke.

Web-Based Data to Quantify Meteorological and Geographical Effects on Heat Stroke: Case Study in China.

Heat stroke is a serious heat‐related health outcome that can eventually lead to death. Due to the poor accessibility of heat stroke data, the large‐scale relationship between heat stroke and meteorological factors is still unclear. This work aims to clarify the potential relationship between meteorological variables and heat stroke, and quantify the meteorological threshold that affected the severity of heat stroke. We collected daily heat stroke search index (HSSI) and meteorological data for the period 2013–2020 in 333 Chinese cities to analyze the relationship between meteorological variables and HSSI using correlation analysis and Random forest (RF) model. Temperature and relative humidity (RH) accounted for 62% and 9% of the changes of HSSI, respectively. In China, cases of heat stroke may start to occur when temperature exceeds 36°C and RH exceeds 58%. This threshold was 34.5°C and 79% in the north of China, and 36°C and 48% in the south of China. Compared to RH, the threshold of temperature showed a more evident difference affected by altitude and distance from the ocean, which was 35.5°C in inland cities and 36.5°C in coastal cities; 35.5°C in high‐altitude cities and 36°C in low‐altitude cities. Our findings provide a possible way to analyze the interaction effect of meteorological variables on heat‐related illnesses, and emphasizes the effects of geographical environment. The meteorological threshold quantified in this research can also support policymaker to establish a better meteorological warning system for public health.

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.

NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1\u03b2-mediated neuroinflammation

BackgroundPatients with prior illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke.MethodsIn this study, we used a classic animal heat stroke model. Prior infection was mimicked by using lipopolysaccharide (LPS) or lipoteichoic acid (LTA) injection before heat stroke (LPS/LTA 1 mg/kg). Mice survival analysis curve and core temperature (TC) elevation curve were produced. NLRP3 inflammasome activation was measured by using real-time PCR and Western blot. Mice hypothalamus was dissected and neuroinflammation level was measured. To further demonstrate the role of NLRP3 inflammasome, Nlrp3 knockout mice were used. In addition, IL-1β neutralizing antibody was injected to test potential therapeutic effect on heat stroke.ResultsPrior infection simulated by LPS/LTA injection resulted in latent inflammation status presented by high levels of cytokines in peripheral serum. However, LPS/LTA failed to cause any change in animal survival rate or body temperature. In the absence of LPS/LTA, heat treatment induced heat stroke and animal death without significant systemic or neuroinflammation. Despite a decreased level of IL-1β in hypothalamus, Nlrp3 knockout mice demonstrated no survival advantage under mere heat exposure. In animals with prior infection, their heat tolerance was severely impaired and NLRP3 inflammasome induced neuroinflammation was detected. The use of Nlrp3 knockout mice enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1β production with prior infection condition. Furthermore, IL-1β neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke.ConclusionsBased on the above results, NLRP3/IL-1β induced neuroinflammation might be an important mechanistic factor in heat stroke pathology, especially with prior infection. IL-1β may serve as a biomarker for heat stroke severity and potential therapeutic method.

Establishment and effectiveness evaluation of a scoring system for exertional heat stroke by retrospective analysis

BackgroundHeat stroke (HS) is a serious, life-threatening disease. However, there is no scoring system for HS so far. This research is to establish a scoring system that can quantitatively assess the severity of exertional heat stroke (EHS).MethodsData were collected from a total of 170 exertional heat stroke (EHS) patients between 2005 and 2016 from 52 hospitals in China. Univariate statistical methods and comparison of the area under the receiver operating characteristic (ROC) curve (AUC) were used to screen exertional heat stroke score (EHSS) parameters, including but not limited body temperature (T), Glasgow Coma Scale (GCS) and others. By comparing the sizes of the AUCs of the APACHE II, SOFA and EHSS assessments, the effectiveness of EHSS in evaluating the prognosis of EHS patients was verified.ResultsThrough screening with a series of methods, as described above, the present study determined 12 parameters – body temperature (T), GCS, pH, lactate (Lac), platelet count (PLT), prothrombin time (PT), fibrinogen (Fib), troponin I (TnI), aspartate aminotransferase (AST), total bilirubin (TBIL), creatinine (Cr) and acute gastrointestinal injury (AGI) classification – as EHSS parameters. It is a 0–47 point system designed to reflect increasing severity of heat stroke. Low (EHSS< 20) and high scores (EHSS> 35) showed 100% survival and 100% mortality, respectively. We found that AUCEHSS > AUCSOFA > AUCAPACHE II.ConclusionA total of 12 parameters – T, GCS, pH, Lac, PLT, PT, Fib, TnI, AST, TBIL, Cr and gastrointestinal AGI classification – are the EHSS parameters with the best effectiveness in evaluating the prognosis of EHS patients. As EHSS score increases, the mortality rate of EHS patients gradually increases.

Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model

BackgroundImmune challenge is known to increase heat stroke risk, although the mechanism of this increased risk is unclear. ObjectivesWe sought to understand the effect of immune challenge on heat stroke pathology. Patients/MethodsUsing a mouse model of classic heat stroke, we examined the impact of prior viral or bacterial infection on hematological aspects of recovery. Mice were exposed to heat either 48 or 72 hours following polyinosinic:polycytidylic acid (poly I:C) or lipopolysaccharide injection, time points when symptoms of illness (fever, lethargy, anorexia) were minimized or completely absent. ResultsEmploying multivariate supervised machine learning to identify patterns of molecular and cellular markers associated with heat stroke, we found that prior viral infection simulated with poly I:C injection resulted in heat stroke presenting with high levels of factors indicating coagulopathy. Despite a decreased number of platelets in the blood, platelets are large and non‐uniform in size, suggesting younger, more active platelets. Levels of D‐dimer and soluble thrombomodulin were increased in more severe heat stroke, and in cases of the highest level of organ damage markers D‐dimer levels dropped, indicating potential fibrinolysis‐resistant thrombosis. Genes corresponding to immune response, coagulation, hypoxia, and vessel repair were up‐regulated in kidneys of heat‐challenged animals; these correlated with both viral treatment and distal organ damage while appearing before discernible tissue damage to the kidney itself. ConclusionsHeat stroke‐induced coagulopathy may be a driving mechanistic force in heat stroke pathology, especially when exacerbated by prior infection. Coagulation markers may serve as accessible biomarkers for heat stroke severity and therapeutic strategies.

Prior viral illness increases heat stroke severity in mice.

What is the central question of this study? We hypothesized that prior illness would increase the susceptibility to and severity of heat stroke (HS). What is the main finding and its importance? We provide the first experimental evidence, using a mouse model of HS, that recent viral illness increases the severity of HS. Our data indicate that this effect is not attributable to the exacerbation of hyperthermia but is a consequence of ongoing coagulation and systemic inflammatory reactions. Our data suggest that measurement of platelets, cytokines and chemokines before heat exposure might be indicative of susceptibility to HS, with coagulation and inflammation being potential targets for intervention that could improve recovery. It is hypothesized that prior illness exacerbates heat stroke (HS) in otherwise healthy organisms by augmenting hyperthermia during heat exposure or deactivating cellular pathways that protect against organ injury. To test these hypotheses, we injected telemetered male C57BL/6J mice with lipopolysaccharide (LPS; 50µgkg-1 i.p.) or polyinosinic:polycytidylic acid (PIC; 100µg i.p.) as a bacterial or a viral mimic, respectively, with saline (SAL; equivalent volume) as a control. Mice recovered for 48 or 72h before HS (maximal core temperature=42.4°C). Platelet counts, cytokines, chemokines and organ injury were determined 48 or 72h after injection (without heating) or at maximal core temperature and at 1day of recovery from HS. In the absence of heat, PIC induced more robust signs of sickness and increased cytokines and chemokines (TNF-α, RANTES, IP-10 and MIP-1β) at 48h, which was not observed with LPS (P<0.05). Responses of both groups recovered by 72h, although low platelet counts persisted after PIC (P<0.05). Heat-induced hyperthermia was similar among mice injected with SAL, LPS and PIC; however, PIC-injected mice displayed more severe responses during recovery from HS, with reduced survival (48h, 70 versus 100%; P<0.05), deeper and longer post-HS hypothermia, greater reductions in platelets, elevated RANTES, IP-10, IL-6 and TNF-α and greater duodenal injury (P<0.05). By 72h, survival from HS was no longer reduced in PIC-injected mice, although hypothermia, the reduction in platelets and elevated cytokines persisted. Our data indicate that prior illness exacerbates the severity of HS in the absence of signs of illness at the time of heat exposure and suggest that this is attributable to persistent coagulation and inflammatory reactions that might be targets for intervention to improve recovery.

CTTP Reflects the Severity and Prognosis of Heat Stroke

Background: Temperature control plays a pivotal role in patients with heat stroke (HS), but little work has been done sufficiently on the use of temperature control to reflect disease progression. Here, we defined and analyzed the concrete role of effective controlling time for core temperature to physiological level (CTTP), in order to explore a potential index to guide the diagnosis and treatment of HS. Method: According to Chinese physical characteristics and the consensus of chinese experts, we defined CTTP as time interval of HS onset to stabilization of core temperature (rectal temperature) below 37.7℃. From 2010.01 to 2018.06 in our hospital, we collected a total of 28 HS cases with clinical diagnosis and treatment records for analyzing the correlation between CTTP and organ injuries, prognosis, APACHE II score and other indices. Results: There was a significant growth of exertional HS cases year by year, whereas the hospital mortality remained steady over the years, with an overall mortality rate being 17.85%. After analyzing the basic characteristics of CTTP, we found that it didn't obey normal distribution (P 0.05). Moreover, CTTP length determined the number of damaged organs (r=0.494, P=0.008). The top five of damaged organs in HS patients were central nervous system disorder (100%), liver injury (78.57%), renal injury (67.86%), myocardial injury (57.14%) and blood coagulation disorder (53.57%). Furthermore, some patients with organ injuries, such as renal function impairment, myocardial damage, pulmonary infection, had both higher mean and median of CTTP than the couterpart (P 0.05). Most importantly, CTTP was closely correlated with APACHE II score (r=0.888, P<0.001). Conclusion To reduce core body temperature early and rapidly with preventive measures against rebound lays the foundation for HS treatment. CTTP is an efficient indicator for assessing the severity and prognosis of HS. The injury in some organs (such as heart, lung and kidney) is in a CTTP-dependent manner, and these patients can benefit remarkably from CTTP control. Funding Statement: This work was supported by grants from the Science Fund for Distinguished Young Scholars of Sichuan Province (No.2017JQ0012), National Science Funds of China (No.81500208), China Postdoctoral Science Foundation (No.2017M613429), Youth Programme for PLA (17QNP047). Declaration of Interests: No competing financial interests exist. Ethics Approval Statement: The Institutional Review Board of Chengdu Military General Hospital approved this study and waived the requirement of informed consent, and we confirmed that all analyses followed the relevant guidelines and regulations.

Amino Acid‐Based Oral Rehydration Solution Mitigates Exertional Heat Stroke Severity but Does Not Alter the Innate Immune Response

Theadverse sequelae following exertional heat stroke (EHS) is hypothesized to be aconsequence of heat cytotoxicity and endotoxin leakage secondary to increasesin gut permeability. Administration ofspecific amino acids has been shown to tighten the mucosal barrier, reduceparacellular permeability, decrease endotoxin leakage, and suppress the subsequentinflammatory response. The primaryobjective of this study was to determine if an amino acid based oralrehydration solution (AA‐ORS) would increase performance in the heat and dampenthe innate immune response following an EHS protocol when compared to a watercontrol (H2O). To explorethis, C57 BL/6J mice were implanted with temperature transmitters and underwentfour familiarization sessions. On the evening prior to EHS, mice were gavaged with 150 μl of either the AA‐ORS or H2O. The EHS protocol was conducted in an environmental chamber at a temperature of 37.5°C with 30% relative humidity and utilized a forced incremental running protocol. TheEHS protocol continued until neurological symptoms were limiting (core temperature(Tc) 42.2°C ± 0.2 H2O and AA‐ORS). Tissue and blood samples were collected at 0.5, 3, and 24 h post EHS. All mice survived until tissue collection. Performance in the heat was similar between groups as determined by percent dehydration, max speed, distance, time to Tc max, and thermal load (P&gt;0.05). The extent of hypothermia during recovery, a marker of EHS severity, was mitigated with AA‐ORS (P=0.0054). Minimum Tc (AA‐ORS:32.9°C ± 0.4; H2O: 32.1°C ± 0.8; P=0.0020), hypothermia depth (AA‐ORS: 33.3 ±0.5 min; H2O: 32.5 ± 0.8 min; P=0.0024), and hypothermia length (AA‐ORS: 186.9 ± 47.3 min; H2O: 243.6 ± 42.3 min; P=0.0017) were all significantly improved by AA‐ORS. Although AA‐ORS reduced paracellular permeability (4 kDa FITC, Ussing chamber) at both the 30 min and 3 h timepoints (P&lt;0.05), it did not affect the cytokine or chemokine profile (25 plex Luminex panel) in response to EHS at any time point (P&gt;0.05). Inflammation in hypothalamus was alsomeasured as an indication of EHS severity. No differences were seen between AA‐ORS and H2O in mRNA upregulation of IL‐1β, IL‐6, TNFα, MCP‐1, MIP‐1α, MIP‐1β or pattern recognition receptors TLR‐4 and CD14 at the 0.5 or 3 h time points. Further, corticosterone, a hormone that has been shown to suppress the innate immuneresponse, did not differ between treatment groups at any time point. These results suggest that an AA‐ORS improves Tc regulation during EHS recovery, but this dosage had no effect on the systemic inflammatory response that isc haracteristic of EHS. Author views not official US Army or Do Dpolicy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Endogenous genetic risk factor for serious heatstroke: the thermolabile phenotype of carnitine palmitoyltransferase II variant.

AimIn serious heatstroke, elevated body temperature (>40°C) is considered the main cause of illness. Mitochondrial carnitine palmitoyltransferase II (CPT II) plays an important role in adenosine triphosphate (ATP) generation from long‐chain fatty acids, and its thermolabile phenotype of CPT2 polymorphisms leads to ATP production loss under high fever. Whether by heatstroke or influenza, high fever suppresses mitochondrial ATP production in patients with the thermolabile phenotype of CPT2 polymorphisms. We investigated the relation between CPT2 polymorphism and severity of heatstroke with a body temperature of over 40°C.MethodsWe analyzed blood chemistry test results, Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC), Acute Physiologic and Chronic Health Evaluation II, and Sequential Organ Failure Assessment (SOFA) scores, and CPT2 polymorphisms in 24 consecutive patients with severe heatstroke at two university hospitals.ResultsEleven patients carried thermolabile CPT II variants (rs2229291; c.1055T˃G [p.Phe352Cys]) (F352C), and the genotype frequency was greater in heatstroke patients than in healthy volunteers. There was no significant difference in body temperature or blood chemistry data at emergency room arrival between patients with and without the CPT II variants. However, hospital days were longer and initial antithrombin activity was significantly lower in the variant group, suggesting a possible link with early phase vascular endothelial cell dysfunction. The JAAM DIC diagnostic criteria and SOFA scores were also higher in the group. There were no differences in the serum albumin, serum creatine kinase, and fibrin degradation product levels, and platelet counts.ConclusionsIn addition to known risks (e.g., environmental temperature and old age), the CPT II polymorphism [F352C] can be a predisposing genetic risk factor for serious heatstroke with organ disfunction, and lower antithrombin activity.

Effects of fenoldopam on kidney function parameters and its therapeutic efficacy in the management of acute kidney injury in dogs with heatstroke.

BackgroundAcute kidney injury (AKI) is common in dogs, but evidence of efficacy of its treatment is lacking.ObjectiveTo evaluate the efficacy of fenoldopam in the management of AKI.AnimalsForty dogs with naturally occurring heatstroke.MethodsDogs were prospectively enrolled and divided into treatment and the placebo groups (fenoldopam, constant rate infusion [CRI] of 0.1 µg/kg/min or saline, respectively). Urine production (UP) was measured using a closed system. Urinary clearances were performed at 4, 12, and 24 hours after presentation to estimate the effect of fenoldopam on UP, glomerular filtration rate (GFR) and sodium fractional excretion (NaFE).ResultsAt presentation, severity of heatstroke, based on a previously developed scoring system, was similar between the study groups, but was significantly worse in nonsurvivors compared with survivors. Fenoldopam administration was not associated with hypotension. Overt AKI was diagnosed, based on the International Renal Interest Society guidelines in 22/40 (55%) of the dogs. Overall, 14/40 dogs (35%) died, with no significant (P = .507) mortality rate difference between the fenoldopam (6/20 dogs; 30%) and placebo (8/20; 40%) groups. The proportion of dogs with AKI did not differ between the fenoldopam and the placebo groups (9/20; 45% versus 13/20; 65%, respectively; P = .204). There were no differences in UP, GFR, and NaFE between the fenoldopam and the placebo groups.Conclusion and Clinical ImportanceFenoldopam CRI at 0.1 µg/kg/min did not have a clinically relevant effect on kidney function parameters in dogs with severe heatstroke‐associated AKI.

Pretreatment with indomethacin results in increased heat stroke severity during recovery in a rodent model of heat stroke.

It has been suggested that medications can increase heat stroke (HS) susceptibility/severity. We investigated whether the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (INDO) increases HS severity in a rodent model. Core temperature (Tc) of male, C57BL/6J mice (n = 45) was monitored continuously, and mice were given a dose of INDO [low dose (LO) 1 mg/kg or high dose (HI) 5 mg/kg in flavored treat] or vehicle (flavored treat) before heating. HS animals were heated to 42.4°C and euthanized at three time points for histological, molecular, and metabolic analysis: onset of HS [maximal core temperature (Tc,Max)], 3 h of recovery [minimal core temperature or hypothermia depth (HYPO)], and 24 h of recovery (24 h). Nonheated (control) animals underwent identical treatment in the absence of heat. INDO (LO or HI) had no effect on physiological indicators of performance (e.g., time to Tc,Max, thermal area, or cooling time) during heating or recovery. HI INDO resulted in 45% mortality rate by 24 h (HI INDO + HS group). The gut showed dramatic increases in gross morphological hemorrhage in HI INDO + HS in both survivors and nonsurvivors. HI INDO + HS survivors had significantly lower red blood cell counts and hematocrit suggesting significant hemorrhage. In the liver, HS induced cell death at HYPO and increased inflammation at Tc,Max, HYPO, and 24 h; however, there was additional effect with INDO + HS group. Furthermore, the metabolic profile of the liver was disturbed by heat, but there was no additive effect of INDO + HS. This suggests that there is an increase in morbidity risk with INDO + HS, likely resulting from significant gut injury.NEW & NOTEWORTHY This paper suggests that in a translational mouse model, NSAIDs may be counterindicated in situations that put an individual at risk of heat injury. We show here that a small, single dose of the NSAID indomethacin before heat stroke has a dramatic and highly damaging effect on the gut, which ultimately leads to increased systemic morbidity.

Indicators of kidney ischemia/reperfusion injury predict heat stroke severity in a conscious rodent model

Currently there are no specific biological markers capable of differentiating between levels of heatstroke (HS) severity. Ischemia/Reperfusion (I/R) is a known concurrent injury pathway that occurs with HS. I/R is a well‐studied condition, which we believe could be leveraged for the discovery of novel HS severity biomarkers. The renal system is one of the critical organ systems in HS pathophysiology. In the current study we investigated whether five well‐established markers of I/R injury in the kidney could also serve as indicators of systemic HS severity level. In this study radiotelemetry implanted Fischer 344 rats were passively heated to a core temperature (Tc) of 42.0±0.1˚C. Their blood pressure (BP) and heart rate (HR) were also monitored continuously during heating and recovery. The rats were then sacrificed at 24 hrs, at which point tissue and blood samples were collected. Combining physiological data (Tc, HR, BP) and histological analysis of tissues, heat exposed rats were categorized into three groups; mild, moderate and severe. Intercellular adhesion molecule 1 (ICAM‐1), Urea, Creatinine, Endothelin‐1 and Lipocalin were analyzed in the kidney and/or plasma for their efficacy as HS severity markers. The latter three markers showed no significant changes across groups in kidney tissue or plasma. ICAM‐1 concentration in kidney tissues showed a significant rise in the moderate (1150.26±70.47 pg/ml, p&lt;0.01) and severe (1155.66±119.85 pg/ml, p&lt;0.03) groups when compare to the controls (816.88±76.21 pg/ml). Rats in the mild group were not significantly changed from the controls (1127.31±133.88, p&lt;0.06) but did show a strong trend for an increase in ICAM‐1 concentration. Urea levels in the plasma parallel robustly with increases in ICAM‐1 in the kidney, and show a distinct rise in severe (93.380±29.19 mg/dL, p&lt;0.007) and moderate (91.733±20.49 mg/dL, p&lt;0.010) HS populations compared with controls (36.916±1.05 mg/dL). Urea levels in the mild group showed comparable levels as the controls (37.422±2.25 mg/dL, p&lt;0.832). In conclusion, the increase in ICAM‐1 and urea suggest significant I/R injury, while also successfully differentiating between levels of HS severity, demarcating mild HS animals from moderate and severe. With further investigation, these results may lead to improved diagnosis and treatment of HS patients. Author views not official US Army or DoD policy.

Prior Infection and Resultant Coagulopathy Increase Heat Stroke Severity

Anecdotally, it has been suggested that prior viral infection increases heat stroke (HS) susceptibility and severity. HS and systemic infection have both been shown to induce disseminated intravascular coagulation (DIC), a condition associated with hypercoagulation, thrombocytopenia, multiorgan dysfunction, and higher mortality. We hypothesized that injection of the immunostimulant Polyinosinic: polycytidylic acid (PIC;100 μg) 48h or 72h prior to heat exposure (HE; 39.5±0.1°C) would exacerbate systemic inflammation and coagulopathy in a conscious C57BL/6J mouse model and increase HS morbidity. Prior to HE, mice injected with PIC showed significantly lower platelet counts at 48h (211 × 10^9/L) and 72h (324 × 10^9/L) compared to saline controls (604 × 10^9/L; P&lt;0.05). In addition, PIC injected mice showed significantly elevated levels of D‐dimer (48h, 783212 pg/ml; 72h, 587265 pg/ml;P&lt;0.05), thrombin‐antithrombin complexes (TAT) (48h, 8.18 ng/ml; P&lt;0.05), thrombomodulin (48h, 28317 pg/ml; 72h, 28269 pg/ml; P&lt;0.05), and decreased levels of antithrombin III (48h, 36527 ng/ml; P&lt;0.05) compared to controls. These results indicate that prior to any HE, injection with PIC induced thrombocytopenia, coagulation, and fibrinolysis. Although PIC injected mice showed no outward signs of illness, HE 48h or 72h post injection was associated with increased mortality (30% and 10%, respectively), with survivors experiencing greater hypothermia depth (marker of HS severity; 29.5°C) compared to controls (30.9°C; P&lt;0.01). HE also significantly increased D‐dimer levels (48h,953787 pg/ml; 72h, 864400 pg/ml; P&lt;0.003) in PIC injected compared to mice exposed to either PIC or heat (601506 pg/ml) alone. Similarly, PIC plus heat induced significantly higher levels of thrombomodulin (48h, 32444 pg/ml; 72h, 33000pg/ml; P&lt;0.02) than PIC or heat (28029 pg/ml) alone. Thus, PIC injection exacerbated systemic coagulation and fibrinolysis experienced during HE and was associated with increased HS severity and mortality. The thrombocytopenia observed in PIC injected mice may reflect a depression in platelet‐mediated immune function and a reduction in their overall capability to handle a second insult such as HE. Future studies will examine coagulation factors as potential biomarkers for predisposing conditions that increase HS susceptibility as well as any potential coagulopathy interventions or therapeutics to increase HS survival. Author views not official US Army or DOD policy.

Impacts of extremely high temperature and heatwave on heatstroke in Chongqing, China.

Few studies have reported the quantitative association between heat and heatstroke (HS) occurrence, particularly in China. The aim of this study was to quantitatively assess the association between high temperature/heatwave and HS occurrence in Chongqing. The daily HS data from 2009 to 2013 of Chongqing were extracted from Chongqing Center for Disease Control and Prevention. A Zero-inflated Poisson regression model (ZIP) with a logistic distribution was used to quantitatively analyze the impacts of the daily maximum temperature (Tmax) over the threshold on HS occurrence by gender, age, and severity of HS, after controlling for covariates including day of the week (DOW), relative humidity, and daily temperature range. Lag effects up to 10days were analyzed. Heatwave intensity, which was classified into four levels according to the quartile of its values, was calculated by Tmax multiplied the duration of a heatwave. The excess risk of HS during heatwave with different intensity was analyzed. The Tmax threshold for HS was 34°C in Chongqing. After adjusting for potential confounders, strong associations and age-specific lag effects between Tmax and daily HS occurrence were observed. The impacts of Tmax on total HS lasted for 7days (lag0-6), with the highest excess risk (ER) value of 30.5% (95% CI 23.6 and 37.8%) on lag0 with each 1°C increment in Tmax over the threshold. A slightly stronger temperature-HS association was detected in male compared to female. The population over 65years had the highest ER and the younger adults aged 19-35 and 35-55years also showed significant heat-HS associations. The number of daily cases increased with the increasing of duration of heatwave and the peak value occurred on the eleventh day of the heatwave. The excess risk of HS during the heatwave with 1 to 4 level of intensity increased by 2.54, 2.97, 5.61, and 11.3 times, respectively, as compared with that of non-heatwave. Extreme heat is becoming a huge threat to public health due to the strong temperature-HS associations in Chongqing. Climate change with increasing temperatures may make the situation worse. Our results can provide reference for developing and improving relevant public health strategies and early extreme weather and health warning system to prevent and reduce the health risks due to extreme weather and climate change in Chongqing.

Ibuprofen Pre‐Treatment Increases Biomarkers of Heat Stroke Severity and Attenuates Fever during Recovery in Conscious Rats

Heat stroke (HS) is a significant environmental threat to both military and civilian populations. We have shown previously in aconscious rodent model that non‐steroidalanti‐inflammatory drugs (NSAIDs) compound HS induced organ damage. Ibuprofen (IB) is one of the top prescribed NSAIDs globally and there are over 450,000 prescriptions for IB in US War fighter population alone, which does not include non‐prescription use. Yet, the effects of IB on HS morbidity have never been investigated. In the current study, we examined what effect a single pre‐dosage of IB has on physiological parameters during HS recovery in a new exertional heat stroke (EHS) rodent model. Fischer 344 rats were implanted with radio telemetry devices that continuously monitor core temperature (Tc),heart rate (HR), and mean arterial blood pressure (MAP). Rats were given either a single dose(62mg/Kg) of IB or vehicle (V, gum arabic) via oral gavage immediately prior to heating. Rats were then forced run(2–8m/min custom interval program) on a specialized heat‐specific running wheelat an ambient temperature of 37°C until cardiovascular crisis/compensatory failure (HR 608 ± 2 BPM; MAP 179 ± 1 mmHg). Rats were sacrificed at 5 days and organs were harvested for molecular and histological analysis. We found that those animals receiving IB had significantly higher temperatures at a given time point during heating (30 min sheating: IB 40.4 ± 0.1, V 40.0 ± 1 P&lt;0.01; 45mins heating: IB 41.6 ± 0.1, V 41.2 ± 0.1 P&lt;0.05), suggesting a decrease in cooling performance during running. IB increased the incidence of physiological biomarkers of severity; IB was the only group with hypothermia after heating (Tc &lt;37 °C, persisting through 24hrs), and had a significantly decreased MAP at 12 hours (IB= 102 ± 5, V= 119 ± 2, P&lt;0.01). In those IB animals that did not experience hypothermia (60%), IB blunted the normal, mild, hyperthermic response found through 12hrs (IB Avg 37.8°C vs V38.4°C), suggesting for the first time that hyperthermia after EHS is a true febrile response. IB had no effect on control animals (those that were unheated). In conclusion, IB may be decreasing performance during heating, inducing increased morbidity during EHS recovery, and could be altering protective physiologic responses. Author views not official US Army or DoD policy.

Altered hypothalamic inflammatory gene expression correlates with heat stroke severity in a conscious rodent model

It has been suggested that heat-induced hypothalamic damage mediates core temperature (Tc) disturbances during heat stroke (HS) recovery; this is significant as hypothermia and/or fever have been linked to severity and overall pathological insult. However, to date there has been a lack of histological evidence in support of these claims. We hypothesized that local hypothalamic cytokines and/or chemokines, known regulators of Tc, are mediating the elevation in Tc during HS recovery even in the absence of histological damage. In experiment 1, the hypothalamus of Fischer 344 rats was examined for 84 cytokine/chemokine genes (real-time PCR) at multiple time points (Tc,Max, 1, 3, and 10 days) during mild HS recovery. In experiment 2, the hypothalamus of three different HS severities (MILD, moderate [MOD], and severe [SEV]) in rats were examined for the same genes as experiment 1 as well as six oxidative damage markers, at a single intermediate time point (1 day). Systemic cytokines were also analyzed in experiment 2 across the three severities. There were significant alterations in 25 cytokines/chemokines expression at Tc,Max, but little or no changes in expression at longer time points in experiment 1. In experiment 2 there were significant changes in gene expression in SEV rats only, with MILD and MOD rats showing baseline expression at 1 day, despite an absence of systemic cytokine expression in any severity. There was also no change in any oxidative marker of damage at 1 day, regardless of severity. In conclusion, we show only limited changes during long term recovery from HS, but demonstrate differences in hypothalamic gene expression patterns that may be driving HS pathology and morbidity. These findings contribute to our overall understanding of HS pathology in the CNS, as well as providing avenues for future pharmacological intervention.