The significant mechanism and treatments of cell death in heatstroke.

With global warming, extreme environmental heat is becoming a social issue of concern, which can cause adverse health results including heatstroke (HS). Severe heat stress is characterized by cell death of direct heat damage, excessive inflammatory responses, and coagulation disorders that can lead to multiple organ dysfunction (MODS) and even death. However, the significant pathophysiological mechanism and treatment of HS are still not fully clear. Various modes of cell death, including apoptosis, pyroptosis, ferroptosis, necroptosis and PANoptosis are involved in MODS induced by heatstroke. In this review, we summarized molecular mechanism, key transcriptional regulation as for HSF1, NRF2, NF-κB and PARP-1, and potential therapies of cell death resulting in CNS, liver, intestine, reproductive system and kidney injury induced by heat stress. Understanding the mechanism of cell death provides new targets to protect multi-organ function in HS.

Cardiovascular magnetic resonance feature tracking derived strain analysis can predict return to training following exertional heatstroke.

BACKGROUND: Exertional heatstroke (EHS) is increasingly common in young trained soldiers. However, prognostic markers in EHS patients remain unclear. The objective of this study was to evaluate cardiovascular magnetic resonance (CMR) feature tracking derived left ventricle (LV) strain as a biomarker for return to training (RTT) in trained soldiers with EHS. METHODS: Trained soldiers (participants) with EHS underwent CMR cine sequences between June 2020 and August 2023. Two-dimensional (2D) LV strain parameters were derived. At 3 months after index CMR, the participants with persistent cardiac symptoms including chest pain, dyspnea, palpitations, syncope, and recurrent heat-related illness were defined as non-RTT. Multivariable logistic regression analysis was used to develop a predictive RTT model. The performance of different models was compared using the area under curve (AUC). RESULTS: A total of 80 participants (median age, 21 years; interquartile range (IQR), 20-23 years) and 27 health controls (median age, 21 years; IQR, 20-22 years) were prospectively included. Of the 77 participants, 32 had persistent cardiac symptoms and were not able to RTT at 3 months follow-up after experiencing EHS. The 2D global longitudinal strain (GLS) was significantly impaired in EHS participants compared to the healthy control group (-15.8 ± 1.7% vs -16.9 ± 1.2%, P = 0.001), which also showed significant statistical differences between participants with RTT and non-RTT (-15.0 ± 3.5% vs -16.5 ± 1.4%, P < 0.001). 2D-GLS (≤ -15.0%) (odds ratio, 1.53; 95% confidence interval: 1.08, 2.17; P = 0.016) was an independent predictor for RTT even after adjusting known risk factors. 2D-GLS provided incremental prognostic value over the clinical model and conventional CMR parameters model (AUCs: 0.72 vs 0.88, P = 0.013; 0.79 vs 0.88, P = 0.023; respectively). CONCLUSION: Two-dimensional global longitudinal strain (≤ -15.0%) is an incremental prognostic CMR biomarker to predict RTT in soldiers suffering from EHS.

Hyperbaric oxygen therapy attenuates heatstroke-induced hippocampal injury by inhibiting microglial pyroptosis.

Background: Central nervous system (CNS) injury is the most prominent feature of heatstroke and the hippocampus is prone to damage. However, the mechanisms underlying the heatstroke-induced hippocampal injury remain unclear. Hyperbaric oxygen (HBO) therapy prevents CNS injury in heatstroke mice. However, the underlying mechanisms of HBO in heatstroke-induced hippocampal injury remain unclear. This study aimed to elucidate the protective effects of HBO against hippocampal injury and its potential role in microglial pyroptosis in heatstroke rats.Methods: A rat heatstroke model and a heat stress model with a mouse microglial cell line (BV2) were, respectively, used to illustrate the effect of HBO on heat-induced microglial pyroptosis in vivo and in vitro. We used a combination of molecular and histological methods to assess microglial pyroptosis and neuroinflammation both in vivo and in vitro.Results: The results revealed that HBO improved heatstroke-induced survival outcomes, hippocampal injury, and neurological dysfunction in rats. In addition, HBO mitigates microglial pyroptosis and reduces the expression of pro-inflammatory cytokines in the hippocampus of heatstroke rats. In vitro experiments showed that HBO attenuated BV2 cell injury under heat stress. Furthermore, HBO prevented heat-induced pyroptosis of BV2 cells, and the expression of pro-inflammatory cytokines IL-18 and IL-1ß was reduced. Mechanistically, HBO alleviates heatstroke-induced neuroinflammation and hippocampal injury by preventing microglial pyroptosis. Conclusions: In conclusion, HBO attenuates heatstroke-induced neuroinflammation and hippocampal injury by inhibiting microglial pyroptosis.

HMGB1 released from pyroptotic vascular endothelial cells promotes immune disorders in exertional heatstroke.

BACKGROUND AND OBJECTIVE: Exertional heatstroke (EHS) mainly occurs in healthy young people with rapid onset and high mortality. EHS immune disorders can cause systemic inflammatory responses and multiple organ failure; however, the underlying mechanisms remain unclear. As high mobility group box 1 (HMGB1) is a prototypical alarmin that activates inflammatory and immune responses, this study aimed to investigate the effect and mechanism of HMGB1 in the pathogenesis of EHS. METHODS: Peripheral blood mononuclear cell (PBMC) transcriptome sequencing of healthy volunteers, classical heatstroke patients, and EHS patients was performed. A mouse model of EHS was established and murine tissue damage was evaluated by H&E staining. HMGB1 localization and release were visualized using immunofluorescence staining. Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were co-cultured to study the effects of HMGB1 on macrophages. A neutralizing anti-HMGB1 antibody was used to evaluate the efficacy of EHS treatment in mice. RESULTS: Plasma and serum HMGB1 levels were significantly increased in EHS patients or mice. EHS-induced endothelial cell pyroptosis promoted HMGB1 release in mice. HMGB1 derived from endothelial cell pyroptosis enhanced macrophage pyroptosis, resulting in immune disorders under EHS conditions. Administration of anti-HMGB1 markedly alleviated tissue injury and systemic inflammatory responses after EHS. CONCLUSIONS: The release of HMGB1 from pyroptotic endothelial cells after EHS promotes pyroptosis of macrophages and systemic inflammatory response, and HMGB1-neutralizing antibody therapy has good application prospects for EHS.

Lactate combined with SOFA score for improving the predictive efficacy of SOFA score in patients with severe heatstroke.

BACKGROUND: The relationship between lactate levels and multiple organ dysfunction in patients with severe heatstroke remains unclear. In this study, we aimed to elucidate the clinical significance of lactate in severe heatstroke prognosis and assess whether incorporating lactate in the SOFA score improves its predictive efficacy. METHODS: This study was a multicenter retrospective cohort investigation included 275 patients. Logistic regression analysis was performed to examine the relationship between lactate levels and patient outcomes and complications, including acute kidney injury (AKI), disseminated intravascular coagulation (DIC), and myocardial injury. Further, receiver operating characteristic (ROC) curves and clinical decision curve analysis (DCA) were used to evaluate the predictive power of lactate and SOFA scores in severe heatstroke-associated death. Lastly, the Kaplan-Meier survival curve was employed to differentiate the survival rates among the various patient groups. RESULTS: After adjusting for confounding factors, lactate was demonstrated as an independent risk factor for death (OR = 1.353, 95% CI [1.170, 1.569]), AKI (OR = 1.158, 95% CI [1.007, 1.332]), DIC (OR = 1.426, 95% CI [1.225, 1.659]), and myocardial injury (OR = 2.039, 95% CI [1.553, 2.679]). The area under the curve (AUC) of lactate for predicting death from severe heatstroke was 0.7540, with a cutoff of 3.35. The Kaplan-Meier survival curve analysis showed that patients with elevated lactate levels had higher mortality rates. Additionally, the ROC curves demonstrated that combining lactate with the SOFA score provided better predictive efficacy than the SOFA score alone in patients with severe heatstroke (AUC: 0.9025 vs. 0.8773, DeLong test, P < 0.001). Finally, the DCA curve revealed a higher net clinical benefit rate for lactate combined with the SOFA score. CONCLUSIONS: Lactate is an independent risk factor for severe heatstroke-related death as well as a risk factor for AKI, DIC, and myocardial injury associated with severe heatstroke. Thus, combining lactate with the SOFA score can significantly improve its predictive efficacy in patients with severe heatstroke.

Howler Monkey Die-Off in Southern Mexico.

In May and June 2024, a die-off of Mexican mantled howler monkeys (Alouatta palliata mexicana) occurred in southern Mexico. This commentary documents the event, attributing it to extreme heatwaves, drought, wildfires, and habitat impoverishment. Despite their reported resilience to habitat disturbances, mantled howler monkey mortality rate in some areas reached 31%. Key evidence points to heatstroke as the primary cause of death, exacerbated by limited hydration and reduced dietary diversity in disturbed habitats. Immediate responses included community-led rescues (e.g., hydrating the monkeys), coordination of rescue activities by nongovernmental organizations (NGOs) (e.g., managing donations), involvement of scientists (e.g., monitoring of primate populations), and assistance from government officials (e.g., providing legal support for animal management). This event underscores the urgency of developing action plans to prevent and attend future crises. Among other actions, we highlight (i) establishing primate care infrastructure with medical and rehabilitation centers; (ii) developing protocols and training programs to ensure rapid crisis response; (iii) fostering collaboration among government, NGOs, and academic institutions for effective crisis management; and (iv) developing targeted research on climate change impacts, predictive models, and long-term health monitoring. We emphasize the critical need for coordinated conservation efforts to protect wild primates and maintain natural ecosystem resilience in the face of escalating climate challenges.

Risk factors for heat-related illness resulting in death or hospitalization in the oil and gas extraction industry.

Many oil and gas extraction (OGE) activities occur in high-heat environments, resulting in a significant risk of heat-related illness among outdoor workers in this industry. This report highlights cases of occupational heat-related illness that resulted in death and identifies common risk factors for heat-related fatalities and hospitalizations among OGE workers. Two databases maintained by the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) were reviewed to identify heat-related fatalities, hospitalizations, and associated risk factors among OGE workers. Nine fatalities and associated risk factors were identified during 2014-2019 from NIOSH's Fatalities in Oil and Gas Extraction (FOG) Database. Risk factors identified included those commonly associated with heat-related fatalities: new workers not acclimatized to heat, inadequate heat stress training, and underlying hypertension or cardiovascular disease. Of particular note, substance use was identified as a significant risk factor as more than half of the fatalities included a positive postmortem test for amphetamines or methamphetamines. Fifty heat-related hospitalizations were identified from OSHA's Severe Injury Report Database during January 2015-May 2021. Heat stress has been and will continue to be an important cause of fatality and adverse health effects in OGE as hot outdoor working conditions become more common and extreme. More emphasis on heat stress training, acclimatization regimens, medical screening, and implementation of workplace-supportive recovery programs may reduce heat-related fatalities and injuries in this industry.

Severe Hyperthermia in Mountaineering: Coincidence of Heat Stroke and Infection.

Heat illness is a condition that is sometimes seen in those undertaking physical activities. This case report focuses on a female hiker who developed heat stroke during a trek in the Dachstein region of Upper Austria. The patient's presentation was initially unclear and could only be confirmed by the use of a thermometer. This had a significant impact on the medical decision-making process during a complex rescue operation.

A newly proposed heatstroke-induced coagulopathy score in patients with heat illness: A multicenter retrospective study in China.

PURPOSE: In patients with heatstroke, disseminated intravascular coagulation (DIC) is associated with greater risk of in-hospital mortality. However, time-consuming assays or a complex diagnostic system may delay immediate treatment. Therefore, the present study proposes a new heatstroke-induced coagulopathy (HIC) score in patients with heat illness as an early warning indicator for DIC. METHODS: This retrospective study enrolled patients with heat illness in 24 Chinese hospitals from March 2021 to May 2022. Patients under 18 years old, with a congenital clotting disorder or liver disease, or using anticoagulants were excluded. Data were collected on demographic characteristics, routine blood tests, conventional coagulation assays and biochemical indexes. The risk factors related to coagulation function in heatstroke were identified by regression analysis, and used to construct a scoring system for HIC. The data of patients who met the diagnostic criteria for HIC and International Society on Thrombosis and Haemostasis defined-DIC were analyzed. All statistical analyses were performed using SPSS 26.0. RESULTS: The final analysis included 302 patients with heat illness, of whom 131 (43.4%) suffered from heatstroke, including 7 death (5.3%). Core temperature (OR = 1.681, 95% CI 1.291 - 2.189, p < 0.001), prothrombin time (OR = 1.427, 95% CI 1.175 - 1.733, p < 0.001) and D-dimer (OR = 1.242, 95% CI 1.049 - 1.471, p = 0.012) were independent risk factors for heatstroke, and therefore used to construct an HIC scoring system because of their close relation with abnormal coagulation. A total score ≥ 3 indicated HIC, and HIC scores correlated with the score for International Society of Thrombosis and Hemostasis -DIC (r = 0.8848, p < 0.001). The incidence of HIC (27.5%) was higher than that of DIC (11.2%) in all of 131 heatstroke patients. Meanwhile, the mortality rate of HIC (19.4%) was lower than that of DIC (46.7%). When HIC developed into DIC, parameters of coagulation dysfunction changed significantly: platelet count decreased, D-dimer level rose, and prothrombin time and activated partial thromboplastin time prolonged (p < 0.05). CONCLUSIONS: The newly proposed HIC score may provide a valuable tool for early detection of HIC and prompt initiation of treatment.

Calcitonin gene-related peptide inhibits neuronal apoptosis in heatstroke rats via PKA/p-CREB pathway.

PURPOSE: The incidence of heatstroke (HS) is not particularly high; however, once it occurs, the consequences are serious. It is reported that calcitonin gene-related peptide (CGRP) is protective against brain injury in HS rats, but detailed molecular mechanisms need to be further investigated. In this study, we further explored whether CGRP inhibited neuronal apoptosis in HS rats via protein kinase A (PKA)/p-cAMP response element-binding protein (p-CREB) pathway. METHODS: We established a HS rat model in a pre-warmed artificial climate chamber with a temperature of (35.5 ± 0.5) °C and a relative humidity of 60% ± 5%. Heatstress was stopped once core body temperature reaches above 41 °C. A total of 25 rats were randomly divided into 5 groups with 5 animals each: control group, HS group, HS+CGRP group, HS+CGRP antagonist (CGRP8-37) group, and HS+CGRP+PKA/p-CREB pathway blocker (H89) group. A bolus injection of CGRP was administered to each rat in HS+CGRP group, CGRP8-37 (antagonist of CGRP) in HS+CGRP8-37 group, and CGRP with H89 in HS+CGRP+H89 group. Electroencephalograms were recorded and the serum concentration of S100B, neuron-specific enolase (NSE), neuron apoptosis, activated caspase-3 and CGRP expression, as well as pathological morphology of brain tissue were detected at 2 h, 6 h, and 24 h after HS in vivo. The expression of PKA, p-CREB, and Bcl-2 in rat neurons were also detected at 2 h after HS in vitro. Exogenous CGRP, CGRP8-37, or H89 were used to determine whether CGRP plays a protective role in brain injury via PKA/p-CREB pathway. The unpaired t-test was used between the 2 samples, and the mean ± SD was used for multiple samples. Double-tailed p < 0.05 was considered statistically significant. RESULTS: Electroencephalogram showed significant alteration of θ (54.50 ± 11.51 vs. 31.30 ± 8.71, F = 6.790, p = 0.005) and α wave (16.60 ± 3.21 vs. 35.40 ± 11.28, F = 4.549, p = 0.020) in HS group compared to the control group 2 h after HS. The results of triphosphate gap terminal labeling (TUNEL) showed that the neuronal apoptosis of HS rats was increased in the cortex (9.67 ± 3.16 vs. 1.80 ± 1.10, F = 11.002, p = 0.001) and hippocampus (15.73 ± 8.92 vs. 2.00 ± 1.00, F = 4.089, p = 0.028), the expression of activated caspase-3 was increased in the cortex (61.76 ± 25.13 vs. 19.57 ± 17.88, F = 5.695, p = 0.009) and hippocampus (58.60 ± 23.30 vs. 17.80 ± 17.62, F = 4.628, p = 0.019); meanwhile the expression of serum NSE (5.77 ± 1.78 vs. 2.35 ± 0.56, F = 5.174, p = 0.013) and S100B (2.86 ± 0.69 vs. 1.35 ± 0.34, F = 10.982, p = 0.001) were increased significantly under HS. Exogenous CGRP decreased the concentrations of NSE and S100B, and activated the expression of caspase-3 (0.41 ± 0.09 vs. 0.23 ± 0.04, F = 32.387, p < 0.001) under HS; while CGRP8-37 increased NSE (3.99 ± 0.47 vs. 2.40 ± 0.50, F = 11.991, p = 0.000) and S100B (2.19 ± 0.43 vs. 1.42 ± 0.30, F = 4.078, p = 0.025), and activated the expression caspase-3 (0.79 ± 0.10 vs. 0.23 ± 0.04, F = 32.387, p < 0.001). For the cell experiment, CGRP increased Bcl-2 (2.01 ± 0.73 vs. 2.15 ± 0.74, F = 8.993, p < 0.001), PKA (0.88 ± 0.08 vs. 0.37 ± 0.14, F = 20.370, p < 0.001), and p-CREB (0.87 ± 0.13 vs. 0.29 ± 0.10, F = 16.759, p < 0.001) levels; while H89, a blocker of the PKA/p-CREB pathway reversed the expression. CONCLUSIONS: CGRP can protect against HS-induced neuron apoptosis via PKA/p-CREB pathway and reduce activation of caspase-3 by regulating Bcl-2. Thus CGRP may be a new target for the treatment of brain injury in HS.

Risk factors for brain injury in patients with exertional heatstroke: A 5-year experience.

PURPOSE: Minimal data exist on brain injury in patients with exertional heatstroke (EHS) in developing country. In this study, we explored the risk factors for brain injury induced by EHS 90-day after onset. METHODS: A retrospective cohort study of patients with EHS was conducted in the intensive care unit of the General Hospital of Southern Theater Command of PLA in China from April 2014 to June 2019. Patients were divided into non-brain injury (fully recovered) and brain injury groups (comprising deceased patients or those with neurological sequelae). The brain injury group was further subdivided into a death group and a sequela group for detailed analysis. General information, neurological performance and information on important organ injuries in the acute stage were recorded and analysed. Multivariable logistic regression was used to identify risk factors for brain injury after EHS and mortality risk factors for brain injury, and Kaplan-Meier survival curve was used to evaluate the effect of the neurological dysfunction on survival. RESULTS: Out of the 147 EHS patients, 117 were enrolled, of which 96 (82.1%) recovered, 13 (11.1%) died, and 8 (6.8%) experienced neurological sequelae. Statistically significant differences were found between non-brain injury and brain injury groups in age, hypotension, duration of consciousness disorders, time to drop core body temperature below 38.5°C, lymphocyte counts, platelet counts, procalcitonin, alanine aminotransferase, aspartate aminotransferase, creatinine, cystatin C, coagulation parameters, international normalized ratio, acute physiology and chronic health evaluation II scores, sequential organ failure assessment (SOFA) scores, and Glasgow coma scale scores (all p < 0.05). Multivariate logistic regression showed that age (OR = 1.090, 95% CI: 1.02 - 1.17, p = 0.008), time to drop core temperature (OR = 8.223, 95% CI: 2.30 - 29.40, p = 0.001), and SOFA scores (OR = 1.676, 95% CI: 1.29 - 2.18, p < 0.001) are independent risk factors for brain injury induced by EHS. The Kaplan-Meier curves suggest significantly prolonged survival (p < 0.001) in patients with early Glasgow coma scale score > 8 and duration of consciousness disorders ≤ 24 h. CONCLUSIONS: Advanced age, delayed cooling, and higher SOFA scores significantly increase the risk of brain injury post-EHS. These findings underscore the importance of rapid cooling and early assessment of organ failure to improve outcomes in EHS patients.

Early biomarkers for kidney injury in heat-related illness patients: a prospective observational study at Japanese Self-Defense Force Fuji Hospital.

BACKGROUND: Since heatstroke-induced acute kidney injury (AKI) can progress to chronic kidney disease, it would be useful to detect heatstroke-induced AKI and severe heat-related illness in the early phase. We studied the epidemiology of heat-related illness among patients in the Japanese Ground Self-Defense Force and evaluated the relationship between heat-related illness severity and early urinary biomarkers for AKI. METHODS: We enrolled patients who were diagnosed with heat-related illness at the Self-Defense Force Fuji Hospital from 1 May to 30 September 2020. We compared the urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin levels according to the severity of heat-related illness as defined by positive scores for the Japanese Association of Acute Medicine Heatstroke Working Group (JAAM-HS-WG) criteria (0, mild; 1, moderate; ≥2, severe). RESULTS: Of the 44 patients, kidney injury, defined as serum creatinine (sCr) ≥1.2 mg/dL, was seen in 9 (20.5%) patients. Urinary NAG, NGAL and L-FABP levels were significantly higher in the ≥2 JAAM-HS-WG criteria group than in the 0 group. Furthermore, urinary L-FABP levels were positively correlated with sCr levels. In contrast, the urinary KIM-1 levels showed the best correlation with serum cystatin C (sCysC) among these biomarkers. CONCLUSIONS: We conclude even mild to moderate heatstroke could lead to AKI. Urinary L-FABP is useful for detecting heatstroke-induced AKI and patients with severe heat-related illness requiring immediate treatment. Urinary KIM-1 may detect heatstroke-induced AKI in terms of sCysC, although it was not related to the severity of heat-related illness.

Inflammation, coagulation, and cellular injury in heat-induced shock.

BACKGROUND: The number of heatstroke victims hit record numbers in 2022 as global warming continues. In heat-induced injuries, circulatory shock is the most severe and deadly complication. This review aims to examine the mechanisms and potential approaches to heat-induced shock and the life-threatening complications of heatstroke. METHODS: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning heatstroke, shock, inflammation, coagulopathy, endothelial cell, cell death, and heat shock proteins. RESULTS: Dehydration and heat-induced cardiomyopathy were reported as the major causes of heat-induced shock, although other heat-induced injuries are also involved in the pathogenesis of circulatory shock. In addition to dehydration, the blood volume decreases considerably due to the increased vascular permeability as a consequence of endothelial damage. Systemic inflammation is induced by factors that include elevated cytokine and chemokine levels, dysregulated coagulation/fibrinolytic responses, and the release of damage-associated molecular patterns (DAMPs) from necrotic cell death that cause distributive shock. The cytoprotective heat shock proteins can also facilitate circulatory disturbance under excess heat stress. CONCLUSIONS: Multiple mechanisms are involved in the pathogenesis of heat-induced shock. In addition to dehydration, heat stress-induced cardiomyopathy due to the thermal damage of mitochondria, upregulated inflammation via damage-associated molecular patterns released from oncotic cells, unbalanced coagulation/fibrinolysis, and endothelial damage are the major factors that are related to circulatory shock.

Potential effect of heat adaptation on association between number of heatstroke patients transported by ambulance and wet bulb globe temperature in Japan.

This study analyzed the association between heatstroke incidence and daily maximum wet bulb globe temperature (WBGT) for all 47 prefectures in Japan by age group and severity using time-series analysis, controlling for confounders, such as seasonality and long-term trends. With the obtained association, the relative risk between the reference WBGT (defined as the value at which heatstroke starts to increase) and the daily maximum WBGT at 30 °C (RRwbgt30) of each prefecture were calculated. For the heatstroke data, the daily number of heatstroke patients transported by ambulance at the prefecture level, provided by the Fire and Disaster Management Agency, was utilized. The analysis was conducted for age groups of 7-17 y, 18-64 y, and ≥65 y, and for severity of Deceased, Severe, Moderate (combined as DSM), and Mild. The analysis period was set from May 1 to September 30, 2015-2019. Finally, the correlation between RRwbgt30 and the average daily maximum WBGT during the analysis period (aveWBGTms) of each prefecture was analyzed to examine the regionality of heatstroke incidence. The result showed that RRwbgt30 is negatively correlated with aveWBGTms for the age group 18-64 y and ≥65 y (except for the age group 7-17 y) and for severity. The natural logarithm of the RRwbgt30 of all 47 prefectures ranged from 2.0 to 8.2 for the age group 7-17 y, 1.1 to 4.0 for the age group 18-64 y, 1.8 to 6.0 for the age group ≥65 y, and 1.0 to 3.6 for DSM, and 0.9 to 4.0 for Mild. This regionality can be attributed to the effects of heat adaptation, where people in hotter regions are accustomed to implementing measures against hot environments and are more heat acclimatized than people in cooler regions.

Prediction of climate change impacts on heatstroke cases in Japan's 47 prefectures with the effect of long-term heat adaptation.

One of the negative consequences of increased air temperatures due to global warming is the associated increase in heat-related mortality and morbidity. Studies that focused on future predictions of heat-related morbidity do not consider the effect of long-term heat adaptation measures, nor do they use evidence-based methods. Therefore, this study aimed to predict the future heatstroke cases for all 47 prefectures of Japan, by considering long-term heat adaptation by translating current geographical differences in heat adaptation to future temporal heat adaptation. Predictions were conducted for age groups of 7-17, 18-64, and ≥65 years. The prediction period was set to a base period (1981-2000), mid-21st century (2031-2050), and the end of the 21st century (2081-2100). We found that the average heatstroke incidence (number of patients with heatstroke transported by ambulance per population) in Japan under five representative climate models and three greenhouse gas (GHG) emissions scenarios increased by 2.92- for 7-17 years, 3.66- for 18-64 years, and 3.26-fold for ≥65 years at the end of the 21st century without heat adaptation. The corresponding numbers were 1.57 for 7-17 years, 1.77 for 18-64 years, and 1.69 for ≥65 years with heat adaptation. Furthermore, the average number of patients with heatstroke transported by ambulance (NPHTA) under all climate models and GHG emissions scenarios increased by 1.02- for 7-17 years, 1.76- for 18-64 years, and 5.50-fold for ≥65 years at the end of 21st century without heat adaptation, where demographic changes were considered. The corresponding numbers were 0.55 for 7-17 years, 0.82 for 18-64 years, and 2.74 for ≥65 years with heat adaptation. The heatstroke incidence, as well as the NPHTA, substantially decreased when heat adaptation was considered. Our method could be applicable to other regions across the globe.

Glasgow Coma Scale on admission as predictor of neurological sequelae at discharge and acute respiratory failure in patients with heatstroke.

BACKGROUND: Transient neuronal dysfunction may occur in most brain regions with heatstroke (HS). This study aimed to explore the prognostic significance of initial Glasgow Coma Scale (GCS) scores in HS. METHODS: Retrospective data regarding HS were obtained from six hospitals. The primary outcome was neurological sequelae at discharge. Secondary outcomes included acute respiratory failure (ARF) and intensive care unit (ICU) admission. Logistic regression models and random forest imputation were used to assess the independent association between GCS score and outcomes. Interaction and stratified analyses of body temperature (BT) at 0.5 hours were also conducted. Receiver operating characteristic curves and decision curve analysis were used to estimate prognostic values. RESULTS: Of 206 patients, 44 (21.36%) had neurological sequelae at discharge. The mean ± standard deviation initial GCS score was 8.17 ± 4.05. After adjustment for confounders, GCS, as a continuous variable, was significantly related to neurological sequelae at discharge [odds ratio (OR): 0.65; 95% confidence interval (CI): 0.50-0.85; P = 0.002], ARF (OR: 0.76; 95% CI: 0.66-0.87; P = 0.001), and ICU admission (OR: 0.68; 95% CI: 0.53-0.87; P = 0.003). These relationships were consistent in the random forest imputation cohort. The OR between GCS and neurological sequelae at discharge was much lower (P = 0.048) in participants with BT at 0.5 hours ≤39°C than in those with BT at 0.5 hours >39°C. The GCS and National Early Warning Score (NEWS) had similar prognostic ability for all outcomes, whereas the net benefits were greater with the GCS compared with the NEWS. CONCLUSIONS: Initial GCS score was an independent prognostic factor for neurological sequelae at discharge in HS. Rapid cooling played a positive role in this relationship. Key messages What is already known on this topic Brain damage caused by heatstroke (HS) can be transient or result in irreversible injury. Early recognition of those at risk of death or developing neurological complications is very important for improving the outcomes of HS. What this study adds Initial Glasgow Coma Scale (GCS) score was an independent prognostic factor for neurological sequelae at discharge, acute respiratory failure, and intensive care unit (ICU) admission in HS. Rapid cooling played a positive role in this relationship. How this study might affect research, practice, or policy The GCS upon emergency department admission can be a useful predictor of prognosis in patients with HS.

Protective and immunomodulatory effects of mesenchymal stem cells on multiorgan injury in male rats with heatstroke.

Heatstroke (HS) causes multiple organ dysfunction syndrome (MODS) with a mortality rate of 60% after hospitalization. Currently, there is no effective and targeted approach for the treatment of HS. Despite growing evidence that mesenchymal stem cells (MSCs) may reduce multiorgan damage and improve survival through immunomodulatory effects in several diseases, no one has tested whether MSCs have immunomodulatory effects in heatstroke. The present study focused on pathological changes and levels of the cytokines and immunoglobulins to investigate the mechanisms underlying the protective effect and the anti-inflammatory effects of MSCs. We found that MSCs treatment significantly reduced the 28-day mortality rate (P < 0.05), the levels of hepatic and renal function markers on day 1 (P < 0.01) and the pathological lesion scores of multiple organs in HS rats. The levels of IgG1, IgM, and IgA of the HS + MSC group was significantly higher than that in HS group on days 3 and 28(P < 0.05). In conclusion, MSCs contribute to protecting against multiorgan injury, reducing pro-inflammatory cytokines, stabilizing immunoglobulins, and reducing the mortality rate of HS rats.

Prediction of in-hospital mortality in patients with exertional heatstroke: a 13-year retrospective study.

Hyperactivity of coagulation is common in exertional heatstroke (EHS). Disseminated intravascular coagulation (DIC) is the most severe form of coagulation dysfunction and associated with poor outcome. DIC, temperature and Glasgow coma scale score were identified as independent risk factors for in-hospital mortality by multivariate logistic regression analysis, and we developed a nomogram for predicting in-hospital mortality in a 13-year EHS patient cohort. The nomogram was assessed by calibration curves and bootstrap with 1,000 resamples. The receiver operating characteristic curve was constructed, and the area under the curve (AUC) was compared. Two hundred and ten patients were included. The in-hospital mortality was 9.0%, and the incidence of DIC was 17.6%. The AUC of the nomogram was 0.897 (95% CI 0.848-0.935, p < .0001) and was non-inferior to SOFA and APACHE II scores but superior to SIRS score, which were widely-used score systems of disease severity. The nomogram contributed to the adverse outcome prediction of EHS.

[Expert consensus on the prevention and treatment of heatstroke in children (2023)]. / å„¿ç«¥ä¸­æš‘çš„é˜²æ²»æ–¹æ¡ˆä¸“å®¶å ±è¯†ï¼ˆ2023年）.

Due to the immature development of temperature regulation in the central nervous system, children have a weakened ability to regulate heat and are susceptible to heatstroke, which can lead to organ damage. Based on the evidence evaluation criteria of the Oxford Centre for Evidence-Based Medicine, this expert consensus group evaluated the current evidence on heatstroke in children, and formed this consensus through thorough discussion with the aim of providing reference for the prevention and treatment of heatstroke in children. This consensus includes classifications, pathogenesis, prevention measures, as well as pre-hospital and in-hospital treatment plans for heatstroke in children.

Outer membrane vesicles derived from heatstroke-associated intestinal microbiota promote multiple organ injury in mice.

Multiple organ injury is a common issue in heatstroke (HS); however, the underlying pathogenesis remains unclear. As an early event in HS, intestinal injury is an active participant that drives organ injury. Outer membrane vesicles (OMVs), a group of vesicles shed by unbalanced intestinal microbiota as "danger signals," mediate different functional cargo transport in cells and modulate varying biological events in distant target cells. However, the role of OMVs in HS-mediated organ damage remains unclear. Therefore, this study examined OMV production in HS and explored the effect of regulating multiple organ injury. To construct a mouse model, animals were exposed to hyperthermia. OMVs from the intestinal microbiota of HS and control mice were extracted by standardized differential ultracentrifugation. Thereafter, OMVs were characterized and infused into recipient mice via the tail vein. Cl-amidine (a pan-peptidylarginine deiminase inhibitor and OMV production inhibitor) was injected intraperitoneally (2 mg/kg) 2 h before HS treatment, and the absorption of HS OMVs by different organs was tracked. The effect of OMVs on inducing organ pathological changes, inflammatory infiltration, inflammatory cytokine expression, and serum organ injury biomarkers was demonstrated. HS increased OMV production by intestinal microbiota; OMVs were absorbed by different organs in vivo, and were especially enriched in the liver and lung. Compared to control OMVs, infusion with HS OMVs induced significant organ pathological changes, elevated inflammatory cell (macrophages and neutrophil) infiltration, inflammatory cytokine (TNF-ɑ, IL-1ß, IL-6) expression, as well as serum biomarkers of organ injury. Similarly, inhibition of endogenous OMVs alleviated these organ injury indicators induced by HS. To our knowledge, the present study is the first to illustrate that OMVs induce acute organ impairment during severe HS, offering a foundation for subsequent studies and providing novel therapeutic targets.