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.

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.

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.

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.

Biomarkers of heatstroke-induced organ injury and repair.

NEW FINDINGS: What is the topic of this review? The status and potential role of novel biological markers (biomarkers) that can help identify the patients at risk of organ injury or long-term complications following heatstroke. What advances does it highlight? Numerous biomarkers were identified related to many aspects of generalized heatstroke-induced cellular injury and tissue damage, and heatstroke-provoked cardiovascular, renal, cerebral, intestinal and skeletal muscle injury. No novel biomarkers were identified for liver or lung injury. ABSTRACT: Classic and exertional heatstroke cause acute injury and damage across numerous organ systems. Moreover, heatstroke survivors may sustain long-term neurological, cardiovascular and renal complications with a persistent risk of death. In this context, biomarkers, defined as biological samples obtained from heatstroke patients, are needed to detect early organ injury, and predict outcomes to develop novel organ preservation therapeutic strategies. This narrative review provides preliminary insights that will guide the development and future utilization of these biomarkers. To this end, we have identified numerous biomarkers of widespread heatstroke-associated cellular injury, tissue damage and repair (extracellular heat shock proteins 72 and 60, high mobility group box protein 1, histone H3, and interleukin-1α), and other organ-specific biomarkers including those related to the cardiovascular system (cardiac troponin I, endothelium-derived factors, circulation endothelial cells, adhesion molecules, thrombomodulin and von Willebrand factor antigen), the kidneys (plasma and urinary neutrophil gelatinase-associated lipocalin), the intestines (intestinal fatty acid-binding protein 2), the brain (serum S100ß and neuron-specific enolase) and skeletal muscle (creatine kinase, myoglobin). No specific biomarkers have been identified so far for liver or lung injury in heatstroke. Before translating the identified biomarkers into clinical practice, additional preclinical and clinical prospective studies are required to further understand their clinical utility, particularly for the biomarkers related to long-term post-heatstroke health outcomes.

Serum myoglobin as predictor of acute kidney injury and 90-day mortality in patients with rhabdomyolysis after exertional heatstroke: an over 10-year intensive care survey.

OBJECTIVE: Rhabdomyolysis (RM) in exertional heatstroke (EHS) often leads to multiple organ dysfunction including acute kidney injury (AKI). Studies have shown that serum creatine kinase (CK) >1000 U/L as a serological diagnostic criterion for RM does not reflect the risk of AKI or mortality. METHODS: This longitudinal cohort study included all patients with EHS who were admitted to intensive care unit between January 2008 and June 2019. Serum myoglobin (sMb) was studied as the serological marker of RM and compared with CK. Outcome events were AKI and 90-day mortality. RESULTS: A total of 161 patients were enrolled, of whom 52 (32.3%) had sMb ≥1000 ng/mL. Patients with sMb ≥1000 ng/mL had higher SOFA score, higher APACHE II score, lower GCS score, and higher incidence of disseminated intravascular coagulation, acute myocardial injury, acute liver injury, AKI, and 90-day mortality than patients with sMb <1000 ng/mL. Lymphocytes, neutrophils, D-Dimer were risk factors for AKI in patients with sMb ≥1000 ng/mL. Curve fitting showed a curved relationship between sMb and EHS-induced AKI but not CK. sMb ≥1000 ng/mL showed better predictive ability for AKI (area under curve: 0.786). APACHE II, SOFA, and GCS scores were risk factors for 90-day mortality in patients with sMb ≥1000 ng/mL. CONCLUSION: Serum myoglobin is a better predictor of AKI and 90-day mortality than CK in patients with RM after EHS.

Usefulness of sequential organ failure assessment score on admission to predict the 90-day mortality in patients with exertional heatstroke: An over 10-year intensive care survey.

BACKGROUND AND OBJECTIVES: Despite a growing understanding of exertional heatstroke (EHS), there is a paucity of clinical evidence for risk-stratification of patients with EHS. The objective of this study was to identify an appropriate scoring system for prognostic assessment of EHS. METHODS: This was a retrospective cohort study of all patients with EHS admitted to intensive care unit (ICU) of the General Hospital of Southern Theatre Command of PLA between October 2008 and May 2019. Inflammatory indices and organ function parameters at admission, the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, Sequential Organ Failure Assessment (SOFA) scores, and Glasgow Coma Scale (GCS) score were collected. Risk factors for 90-day mortality were identified using multivariate Cox proportional hazard risk regression model. RESULTS: 189 patients (all male) were finally included, with a median age of 21.0 years (IQR 19.0-27.0), median APACHE II score of 11.0 (IQR 8.0-16.0), median SOFA score of 3.0 (IQR 2.0-6.0), and median GCS score of 12.0 (IQR 7.0-14.0). There were 166 survivors (87.8%) and 23 non-survivors (12.2%). Compared with survivor group, non-survivors had higher incidence of severe organ damage, including rhabdomyolysis (46.1% vs 63.6%), disseminated intravascular coagulation (25.6% vs 90.0%), acute liver injury (69.4% vs 95.7%), and acute kidney injury (36.6% vs 95.7%). Multivariate Cox risk regression model showed that SOFA score was an independent risk factor for 90-day mortality, with an optimal cutoff score of 7.5. CONCLUSIONS: SOFA score may be a clinically useful predictor of death in EHS. Prospective studies are required to confirm the effectiveness of SOFA score and the optimal cutoff level.

Association of D-dimer and acute kidney injury associated with rhabdomyolysis in patients with exertional heatstroke: an over 10-year intensive care survey.

Patients with rhabdomyolysis (RM) following exertional heatstroke (EHS) are often accompanied by dysfunction of coagulation and acute kidney injury (AKI). The purpose of this study was to investigate the relationship between D-dimer and AKI in patients with RM following EHS. A retrospective study was performed on patients with EHS admitted to the intensive care unit over 10-year. Data including baseline clinical information at admission, vital organ dysfunction, and 90-day mortality were collected. A total of 84 patients were finally included, of whom 41 (48.8%) had AKI. AKI patients had more severe organ injury and higher 90-day mortality (34.1 vs.0.0%, p < 0.001) than non-AKI patients. Multivariate logistic analysis showed that D-dimer (OR 1.3, 95% CI 1.1-1.7, p = 0.018) was an independent risk factor for AKI with RM following EHS. Curve fitting showed a curve relationship between D-dimer and AKI. Two-piecewise linear regression showed that D-dimer was associated with AKI in all populations (OR 1.3, 95% CI 1.2-1.5, p < 0.001) when D-dimer <10.0 mg/L, in RM group (OR 1.3, 95% CI 1.1-1.5, p < 0.001) when D-dimer >0.4 mg/L, in the non-RM group (OR 6.4, 95% CI 1.7-23.9, p = 0.005) when D-dimer <1.3 mg/L and D-dimer did not increase the incidence of AKI in the non-RM group when D-dimer >1.3 mg/L. AKI is a life-threatening complication of RM following EHS. D-dimer is associated with AKI in critically ill patients with EHS. The relationship between D-dimer and AKI depends on whether RM is present or not.

Renoprotective effect of oral rehydration solution III in exertional heatstroke rats.

AIM: Exertional heastroke (EHS) can lead to acute kidney injury. Oral rehydration solution III (ORS III), recommended by WHO in 2004, is used to rehydrate children with gastroenteritis. This study aimed to characterize the renoprotective effect of ORS III in EHS rats. METHODS: Rats were randomly divided into Group Control, Group EHS, Group EHS + Water, and Group EHS + ORS. Thirty minutes before the experiment, ORS III was orally administrated to Group EHS + ORS, Water was given to Group EHS + Water. Rats from Group EHS, Group EHS + Water and Group EHS + ORS were then forced to run until they fatigued. Core temperature (Tc) was monitored and 40.5 °C was considered as the onset of heatstroke. Serum creatinine (SCr), blood urea nitrogen (BUN) were measured using an automated biochemical analyzer. Serum neutrophil gelatinase-associated lipocalin (NGAL) was measured using an NGAL ELISA Kit. Light microscopy was used for kidney structural analysis. RESULTS: SCr level in Group EHS was no different from Group Control (p > .05), while BUN and NGAL levels in Group EHS were higher than Group Control (p <.001, p < .001). SCr, BUN and NGAL concentrations in group EHS + Water were no different from Group EHS (p > .05). SCr, BUN levels in Group EHS + ORS were no different from Group EHS (p > .05). But NGAL levels were significant in these two groups (p = .012). Renal histopathologies of rats in Group EHS and Group EHS + Water showed flattened lumens filled with eosinophilic materials. The damage was milder in Group EHS + ORS, in which injured tubules showed degeneration of the tubular epithelium and sloughing of the brush border membrane. CONCLUSION: ORS III could alleviate the kidney injury in EHS rats.

Extracellular and cellular Hsp72 differ as biomarkers in acute exercise/environmental stress and recovery.

Stress-inducible Hsp72 is a potential biomarker to track risk of exertional heat illness during exercise/environmental stress. Characterization of extracellular (eHsp72) vs cellular Hsp72 (iHsp72) responses is required to define the appropriate use of Hsp72 as a reliable biomarker. In each of four repeat visits, participants (n = 6 men, 4 trials; total n = 24): (a) passively dehydrated overnight, (b) exercised (2 h) with no fluid in a hot, humid environmental chamber, (c) rested and rehydrated (1 h), (d) maximally exercised for 0.5 h, and (e) returned after 24 h of at-home recovery and rehydration. We measured rectal temperature, hydration status (% body mass loss, urine markers, serum osmolality), and Hsp72 (ELISA, flow cytometry. eHsp72 (circulating) and iHsp72 (CD3+ PBMCs) correlated (P < 0.05) with markers of heat, exercise, and dehydration stresses. eHsp72 immediately post-exercise (>15% above baseline, P < 0.05) decreased back to baseline levels by 1 h post-exercise, but iHsp72 expression continued to rise and remained elevated 24 h post-exercise (~2.5-fold baseline, P < 0.05). These data suggest that in addition to the classic physiological biomarkers of exercise heat stress, using cellular Hsp72 as an indicator of lasting effects of stress into recovery may be most appropriate for determining long-term effects of stress on risk for exertional heat illness.

Serum procalcitonin levels are associated with rhabdomyolysis following exertional heatstroke: an over 10-year intensive care survey.

BACKGROUND: Heatstroke has become a common emergency event in hospitals. Procalcitonin (PCT) is used as a biomarker of infection in the emergency department (ED), but its role in rhabdomyolysis (RM) following exertional heatstroke (EHS) remains unclear. METHODS: A retrospective cohort study enrolled patients with EHS from the intensive care unit (ICU). We collected RM biomarkers, inflammation markers, critical disease scores at admission, 24 h, 48 h, and discharge, and 90-day mortality. Correlation analysis, linear regression and curve fitting were used to identify the relationship between PCT and RM. RESULTS: A total of 162 patients were recruited and divided into RM (n=56) and non-RM (n=106) groups. PCT was positively correlated with myoglobin (Mb), acute hepatic injury, disseminated intravascular coagulation (DIC), Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score, with correlation coefficients of 0.214, 0.237, 0.285, 0.454, and 0.368, respectively (all P<0.05). Interestingly, the results of curve fitting revealed a nonlinear relationship between PCT and RM, and a two-piecewise linear regression model showed that PCT was related to RM with an odds ratio of 1.3 and a cut-off of <4.6 ng/mL. Survival analysis revealed that RM was associated with higher mortality compared to non-RM cases (P=0.0093). CONCLUSION: High serum PCT concentrations are associated with RM after EHS in critically ill patients. Elevated PCT concentrations should be interpreted cautiously in patients with EHS in the ED.

Monocyte HLA-DR level on admission predicting in-hospital mortality rate in exertional heatstroke: A 12-year retrospective study.

BACKGROUND: Exertional heatstroke (EHS), a fatal illness, pronounces multiple organ dysfunction syndrome (MODS) and high mortality rate. Currently, no ideal factor prognoses EHS. Decreased monocyte human leukocyte-DR antigen (mHLA-DR) has been observed in critically ill individuals, particularly in those with sepsis. While most research focus on the pro-inflammatory response exploration in EHS, there are few studies related to immunosuppression, and no report targeted on mHLA-DR in EHS. The present study tried to explore the prognostic value of mHLA-DR levels in EHS patients. METHODS: This was a single-center retrospective study. Clinical data of EHS patients admitted to the intensive care unit of the General Hospital of Southern Theatre Command between January 1, 2008, and December 31, 2020, were recorded and analyzed. RESULTS: Seventy patients with 54 survivors and 16 nonsurvivors were ultimately enrolled. Levels of mHLA-DR in the nonsurvivors (41.8% [38.1-68.1]%) were significantly lower than those in the survivors (83.1% [67.6-89.4]%, p < 0.001). Multivariate logistic regression indicated that mHLA-DR (odds ratio [OR] = 0.939; 95% confidence interval [CI]: 0.892-0.988; p = 0.016) and Glasgow coma scale (GCS) scores (OR = 0.726; 95% CI: 0.591-0.892; p = 0.002) were independent risk factors related with in-hospital mortality rate in EHS. A nomogram incorporated mHLA-DR with GCS demonstrated excellent discrimination and calibration abilities. Compared to the traditional scoring systems, the prediction model incorporated mHLA-DR with GCS had the highest area under the curve (0.947, 95% CI: [0.865-0.986]) and Youden index (0.8333), with sensitivity of 100% and specificity of 83.33%, and a greater clinical net benefit. CONCLUSION: Patients with EHS were at a risk of early experiencing decreased mHLA-DR early. A nomogram based on mHLA-DR with GCS was developed to facilitate early identification and timely treatment of individuals with potentially poor prognosis.

Contribution of medical resonance imaging in the return to physical activity after exertional rhabdomyolysis a case report.

INTRODUCTION: Exertional rhabdomyolysis (ER) is the breakdown of muscle cells that occurs after intensive physical activity. Although a cautious and gradual return to physical activity (RTPA) is recommended after an episode of ER, physical sequelae are reported long afterwards. CASE REPORT: We present the case of a 31-year-old untrained amateur runner with no prior medical history who developed heat stroke, ER, and acute kidney failure on the occasion of a half-marathon. Three months later, whereas the patient was symptom-free and CK levels were normal, an MRI revealed typical signs of rhabdomyolysis, which normalized thereafter. DISCUSSION: Given that clinical and biological data inform RTPA decisions, the delay between clinical biological and MRI normalization may cause an RTPA to be initiated prior to full muscle recovery, which could account for the symptoms' prolonged persistence. In sportspeople who have recovered and their CK blood levels are returned to normal, MRI data could defer the RTPA if MRI abnormalities persist or, conversely, give it the green light.

In the event of exertional rhabdomyolysis following a race, the presence of muscular lesions on MRI, even if the patient feels healed and creatine kinase levels have returned to normal, should postpone the return to physical activity.

A nomogram based on lymphocyte percentage for predicting hospital mortality in exertional heatstroke patients: a 13-year retrospective study.

BACKGROUND: Exertional heatstroke (EHS) is a life-threatening disease without ideal prognostic markers for predicting hospital mortality. METHODS: This is a single-center retrospective study. Clinical data from EHS patients admitted to the Intensive Care Unit (ICU) of the General Hospital of Southern Theatre Command between January 1, 2008, and December 31, 2020, were recorded and analyzed. Univariate and multivariate logistic regression were used to identify the factors for mortality. The prediction model was developed with the prognostic markers, and a nomogram was established. RESULTS: The study ultimately enrolled 156 patients, and 15 (9.6%) of patients died before discharge. The lymphocyte count (Lym) and percentage (Lym%) were significantly lower in non-survivors (P<0.05). The univariate and multivariate logistic regression analyses indicated that Lym% at the third day of admission (Lym% D3) (OR=0.609, 95%CI: 0.454-0.816) and hematocrit (HCT) (OR=0.908, 95%CI: 0.834-0.988) were independent protective factors for hospital mortality. A nomogram incorporating Lym% D3 with HCT was developed and demonstrated good discrimination and calibration ability. The comparison between the prediction model and scoring systems revealed that the prediction model had the largest area under the curve (AUC) (0.948, 95%CI: 0.900-0.977), with 100.00% sensitivity and 83.69% specificity, and a greater clinical net benefit. CONCLUSION: Severe EHS patients had a higher risk of experiencing prolonged lymphopenia. A nomogram based on Lym% D3 and HCT was developed to facilitate early identification and timely treatment of patients with potentially unfavorable prognoses.

Excellent Rectal Temperature Cooling Rates in the Polar Life Pod Consistent With Stationary Tubs.

CONTEXT: Several tools exist to reduce rectal temperature (TREC) quickly for patients experiencing exertional heatstroke (EHS). Stationary tubs effectively treat EHS but are bulky and impractical in some situations. More portable cold-water immersion techniques, such as tarp-assisted cooling with oscillation, are gaining popularity because of their benefits (eg, less water needed, portability). The Polar Life Pod (PLP) may be another portable way to reduce TREC, but few researchers have examined its effectiveness. OBJECTIVES: To determine whether the PLP and stationary tub reduced TREC at acceptable or ideal rates, whether TREC cooling rates differed by method, and how participants felt before, during, and after cooling. DESIGN: Randomized crossover study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirteen individuals (8 men, 5 women; age = 21 ± 2 years, mass = 73.99 ± 11.24 kg, height = 176.2 ± 11.1 cm). INTERVENTION(S): Participants exercised in the heat until TREC was 39.5°C. They immersed themselves in either the PLP (202.7 ± 23.8 L, 3.2 ± 0.6°C) or a stationary tub (567.8 ± 7.6 L, 15.0 ± 0.1°C) until TREC was 38°C. Thermal sensation and environmental symptom questionnaire (ESQ) responses were recorded before, during, and after exercise and cooling. MAIN OUTCOME MEASURE(S): Rectal temperature cooling rates, thermal sensation, and ESQ responses. RESULTS: Participants had similar exercise durations (PLP = 41.6 ± 6.9 minutes, tub = 42.2 ± 9.3 minutes, t12 = 0.5, P = .31), thermal sensation scores (PLP = 7.0 ± 0.5, tub = 7.0 ± 0.5, P > .05), and ESQ scores (PLP = 25 ± 13, tub = 29 ± 14, P > .05) immediately postexercise each day. Although TREC cooling rates were excellent in both conditions, the PLP cooled faster than the stationary tub (PLP = 0.28 ± 0.09°C/min, tub = 0.20 ± 0.09°C/min, t12 = 2.5, P = .01). Thermal sensation in the PLP condition was lower than that in the tub condition halfway through cooling (PLP = 1 ± 1, tub = 2 ± 1, P < .05) and postcooling (PLP = 2 ± 1, tub = 3 ± 1, P < .05). The ESQ scores were higher for PLP than for the stationary tub postcooling (PLP = 25 ± 14, tub = 12 ± 9, P < .05). CONCLUSIONS: The PLP and the stationary tub cooled individuals with hyperthermia at ideal rates for treating patients with EHS (ie, >0.16°C/min). The PLP may be an effective tool for treating EHS when limited water volumes and portability are concerns. Clinicians should have rewarming tools and strategies (eg, heating blankets) available to improve patients' comfort after PLP use.

Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke.

Background and Objectives: Myoglobin released by rhabdomyolysis (RM) is considered to be involved in pathogenesis of kidney disease caused by crush injury, but whether high level of serum myoglobin predisposes patients to acute kidney injury (AKI) and its molecular mechanisms are still unclear in exertional heatstroke (EHS). We aimed to determine the association and potential mechanism of myoglobin and AKI, and further investigate the targeted therapeutic agents for myoglobinemia. Methods: Serum myoglobin concentrations in patients with EHS were measured at admission, 24 h and 48 h after admission and discharge. The risk of AKI at 48 h was the primary outcome; the secondary outcome was composite outcome events with myoglobin levels and AKI at discharge and death at 90 days. In experimental studies, we further investigated the mechanisms of human kidney proximal tubular (HK-2) cells that were exposed to human myoglobin under heat stress conditions and the effect of baicalein. Results: Our measurements showed that the highest myoglobin quartile (vs. the lowest) had an adjusted odds ratio (OR) of 18.95 (95% confidence interval [CI], 6.00-59.83) for AKI and that the OR (vs. quartile 2) was 7.92 (95% CI, 1.62-38.89) for the secondary outcome. The survival rate of HK-2 cells treated with myoglobin under heat stress was significantly decreased, and the production of Fe2+ and reactive oxygen species (ROS) was markedly increased, accompanied by changes in ferroptosis proteins, including increased p53, decreased SLC7A11 and GPX4, and alterations in endoplasmic reticulum stress (ERS) marker proteins. Treatment with baicalein attenuated HK-2 cell ferroptosis induced by myoglobin under heat stress through inhibition of ERS. Conclusions: High myoglobin was associated with AKI in the EHS, and its mechanisms involved ERS-associated ferroptosis. Baicalein may be a potential therapeutic drug for the treatment of AKI in patients with high myoglobin induced by rhabdomyolysis following EHS.

Proteomics analyses of acute kidney injury biomarkers in a rat exertional heat stroke model.

The frequency of exertional heat stroke (EHS) increases with the gradual elevation of global temperatures during summer. Acute kidney injury (AKI) is a common complication of EHS, and its occurrence often indicates the worsening of a patient's condition or a poor prognosis. In this study, a rat model of AKI caused by EHS was established, and the reliability of the model was evaluated by HE staining and biochemical assays. The expression of kidney tissue proteins in the EHS rats was analyzed using label-free liquid chromatography-tandem mass spectrometry. A total of 3,129 differentially expressed proteins (DEPs) were obtained, and 10 key proteins were finally identified, which included three upregulated proteins (Ahsg, Bpgm, and Litaf) and seven downregulated proteins (medium-chain acyl-CoA synthetase 2 (Acsm2), Hadha, Keg1, Sh3glb1, Eif3d, Ambp, and Ddah2). The qPCR technique was used to validate these 10 potential biomarkers in rat kidney and urine. In addition, Acsm2 and Ahsg were double-validated by Western blotting. Overall, this study identified 10 reliable biomarkers that may provide potential targets for the treatment of AKI caused by EHS.

Immune Cells Characteristics and Their Prognostic Effects in Exertional Heatstroke Patients: A Retrospective Cohort Study.

Background: Exertional heatstroke (EHS) remains a major problem for those who take strenuous physical activity. Inflammation and immune dysfunction were thought to be crucial to the pathophysiological process of heatstroke. The present study was aimed to investigate the dynamic changes of the immune cells in patients with EHS and determine their prognostic effects to provide the clinical evidence of the above process. Methods: This single-center retrospective cohort study collected all patients with EHS admitted to the intensive care unit (ICU) of the General Hospital of Southern Theater Command of PLA from October 2008 to May 2019. The dynamic changes of the main immune cell count and ratio were collected, including white blood cell (WBC), neutrophil, monocyte, and lymphocyte. The neutrophil-to-lymphocyte ratios (NLR) were calculated by the neutrophil count/lymphocyte count × 100%. The main outcome was 90-day mortality. Results: A total of 189 patients were enrolled. For survivors, after 24 h, the WBC and neutrophil counts began to decrease, and they were back to normal in 72 h. In addition, the lymphocyte counts were within normal limits all the time. For non-survivors, the WBC and neutrophil counts were continuous over the normal range, while the lymphocyte count and the ratio began to decrease after 24 h and were continuously low in the following days. Receiver operating characteristic (ROC) curves analysis showed that increased neutrophils and decreased lymphocytes were associated with the poor prognosis of the patients. A prediction model based on immune cell counts and ratios was constructed, and the lymphocyte count was accounted for the maximum weight. Conclusions: In patients with EHS, increased neutrophils and decreased lymphocytes were associated with the poor prognosis. The lymphocyte count at 72 h after admission was the most important prognostic factor.

A mouse model of exertional heatstroke-related acute kidney injury.

Background: Acute kidney injury (AKI) is a common complication of exertional heat stroke (EHS) with a complex pathogenesis. We established a stable mouse model of EHS-related AKI (EHS-AKI). Methods: C57BL/6 male mice were divided into 6 groups: Saline Control group, Glycerol Control group, Saline + Sham heat exercise (SHE) group, Saline + Heat exercise (HE) group, Glycerol + SHE group, and Glycerol + HE group. Samples from the Saline Control group and the Glycerol Control group were taken 6 h after the intramuscular injection of saline (4 mL/kg) or glycerol (4 mL/kg) to provide a baseline for comparisons with the other 4 groups. The other 4 groups of mice started exercise 6 h after the intramuscular injection of saline or glycerol, and were sacrificed to collect samples after exercise. Finally, serum and the pathology of kidney and muscle tissues were quantified. Results: There were no differences in the creatinine (Cr), blood urea nitrogen (BUN), creatine kinase (CK), and myoglobin (MYO) levels, but the interleukin 6 (IL-6) level was more increased (P<0.05) in the Glycerol Control group than the Saline Control group at the baseline. The IL-6 levels of the Glycerol + HE group were also higher than those of the Saline + HE groups at 6 and 12 h (P<0.05). The Cr levels at 12 h and 1 day, the BUN levels at 6 h, 12 h, 1 day, and 2 days in the Glycerol+ HE group were higher than the baseline levels (P<0.05). And the renal pathological scores at 6 h, 12 h, 1 day, 2 days, or 3 days were 0.79, 1.29, 1.58, 0.85, and 0.77. However, there was only slight renal pathological injury in the Saline + HE group at 12 h, and 1 day, and the scores were 0.13, and 0.41. The CK level in each group all peaked at 6 h after exercise and higher than the baseline (P<0.05). However, there was no difference in the MYO levels of each group compared to the baseline. Conclusions: We established a stable mouse model of EHS-AKI by conducting a heat exercise after the intramuscular injection of glycerol. Our findings lay the foundation for follow-up clinical and basic research.

American football uniforms elicit thermoregulatory failure during a heat tolerance test.

The Israeli Defense Force's heat tolerance test (HTT) helps clinicians make return-to-activity decisions following exertional heatstroke. Participants fail the test and are "heat intolerant" if rectal temperature (TREC) or heart rate (HR) exceed 38.5°C or 150 bpm, respectively. Ideally, tests assessing athlete heat tolerance would incorporate sport-specific factors (e.g., protective equipment). Because few clothes are worn during a HTT, its ability to assess American football players' heat tolerance may be limited. We hypothesized wearing an American football uniform (PADS) during a HTT would lead to more classifications of heat intolerance. In this randomized, counterbalanced, crossover study, 10 men without recent exertional heat illness (age: 23 ± 3 y; mass: 78.5 ± 10.3 kg; height: 179.6 ± 7.6 cm) completed a standard HTT (CONTROL) or an HTT with PADS donned. TREC and HR were monitored continuously for 2 hours or until TREC reached 39.5°C. We noted when HTT failure criteria occurred. All participants failed the HTT in PADS (n = 2, TREC >38.5°C; n = 8, HR >150 bpm); 5 failed in CONTROL (n = 1, TREC >38.5°C; n = 4, HR >150 bpm). Participants completed more of the HTT before failure in CONTROL than PADS (61.7 ± 23.5 min vs. 43.4 ± 14.2 min; t9 = 1.9, P =.04). The HTT cannot be made more sport-specific by simply donning PADS because PADS impaired thermoregulatory ability and produced more false positive HTT results. Consequently, the HTT should not be the sole determinant of an American football players return-to-activity following heat illness. New methods of testing heat tolerance in American football players are needed since the existing HTT is not sport specific.ABBREVIATIONS: EHS: exertional heatstroke; HR: heart rate; HTT: The Israeli Defense Force's heat tolerance test; PADS: full American football uniform consisting of a helmet; shoulder, knee, thigh, hip and tailbone pads; a jersey top; undergarments; and half-length pants; PHT: probability of heat tolerance; RMANOVA: repeated measures analysis of variance; RPE: rating of perceived exertion; RTP: return to play; TCR: thermal-circulatory ratio; TREC: rectal temperature; VO2max: maximal oxygen consumption.