Hypoxia-inducible factor prolyl hydroxylase inhibitor alleviates heatstroke-induced acute kidney injury by activating BNIP3-mediated mitophagy.

Hypoxia-induced inflammation and apoptosis are important pathophysiological features of heat stroke-induced acute kidney injury (HS-AKI). Hypoxia-inducible factor (HIF) is a key protein that regulates cell adaptation to hypoxia. HIF-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF to increase cell adaptation to hypoxia. Herein, we reported that HIF-PHI pretreatment significantly improved renal function, enhanced thermotolerance, and increased the survival rate of mice in the context of HS. Moreover, HIF-PHI could alleviate HS-induced mitochondrial damage, inflammation, and apoptosis in renal tubular epithelial cells (RTECs) by enhancing mitophagy in vitro and in vivo. By contrast, mitophagy inhibitors Mdivi-1, 3-MA, and Baf-A1 reversed the renoprotective effects of HIF-PHI. Mechanistically, HIF-PHI protects RTECs from inflammation and apoptosis by enhancing Bcl-2 adenovirus E18 19-kDa-interacting protein 3 (BNIP3)-mediated mitophagy, while genetic ablation of BNIP3 attenuated HIF-PHI-induced mitophagy and abolished HIF-PHI-mediated renal protection. Thus, our results indicated that HIF-PHI protects renal function by upregulating BNIP3-mediated mitophagy to improve HS-induced inflammation and apoptosis of RTECs, suggesting HIF-PHI as a promising therapeutic agent to treat HS-AKI.

Effects of isorhamnetin on liver injury in heat stroke-affected rats under dry-heat environments via oxidative stress and inflammatory response.

Isorhamnetin is a natural flavonoid compound, rich in brass, alkaloids, and sterols with a high medicinal value. This study investigated the effects of isorhamnetin on liver injury and oxidative and inflammatory responses in heat-stroke-affected rats in a dry-heat environment. Fifty Sprague Dawley rats were randomly divided into five groups: normal temperature control (NC, saline), dry-heat control (DHC, saline), low-dose isorhamnetin-pretreated (L-AS, 25 mg/Kg), medium-dose isorhamnetin-pretreated (M-AS, 50 mg/Kg), and high-dose isorhamnetin-pretreated (H-AS, 100 mg/Kg) group. Saline was administered to the NC and DHC groups and corresponding concentrations of isorhamnetin were administered to the remaining three groups for 1 week. Blood and liver tissue were analyzed for oxidative stress and inflammation. The liver histopathological injury score, serum liver enzyme (alanine transaminase, aspartate transaminase, and lactate dehydrogenase), liver oxidative stress index (superoxide dismutase [SOD], catalase [CAT], and malondialdehyde), and inflammation index (tumor necrosis factor α [TNF-α], interleukin [IL]-1ß, IL-6, and lipopolysaccharides) were significantly higher in the DHC group than in the NC group (P < 0.05). These index values in the L-AS, M-AS, and H-AS groups were significantly lower than those in the DHC group (P < 0.05). The index values decreased significantly with an increase in the concentration of isorhamnetin (P < 0.05), while the index values of CAT and SOD showed the opposite tendency (P < 0.05). The expression of liver tissue nuclear factor kappa B (NF-κB), caspase-3, and heat shock protein (HSP-70) was higher in the DHC group than in the NC group (P < 0.05). Comparison between the isorhamnetin and DHC groups revealed that the expression of NF-кB and caspase-3 was decreased, while that of HSP-70 continued to increase (P < 0.05). The difference was significant for HSP-70 among all the isorhamnetin groups (P < 0.05); however, the NF-кB and caspase-3 values in the L-AS and H-AS groups did not differ. In summary, isorhamnetin has protective effects against liver injury in heat-stroke-affected rats. This protective effect may be related to its activities concerning antioxidative stress, anti-inflammatory response, inhibition of NF-кB and caspase-3 expression, and enhancement of HSP-70 expression.

Extracellular histones exacerbate heat stroke-induced liver injury by triggering hepatocyte pyroptosis and liver injury via the TLR9-NLRP3 pathway.

BACKGROUND: Severe heat stroke is often complicated by multiple organ failure, including liver injury. Recent evidence indicates that the underlying mechanism constitutes sterile inflammation triggered by cell damage, in which hepatocyte NOD-like receptor family pyrin domain-containing 3 inflammasome activation and pyroptosis play key roles. As extracellular histones act as damage-associated molecular patterns and mediate tissue toxicity and inflammation, we aimed to investigate whether extracellular histones contribute to inducing hepatocyte pyroptosis following heat stroke, promoting the development of liver inflammation and injury, and elucidate the potential underlying mechanisms. METHODS: Exogenous histones were administered to AML-12 murine hepatocytes or male aged 8-12 week mice following hyperthermic treatment (at 39 °C in a chamber with 60 % relative humidity). Prior to heat exposure, endogenous histones were neutralized using neutralizing antibodies, inflammasomes were inhibited by RNA silencing, and Toll-like receptor 9 was modulated using a pharmacological agonist or antagonist. Inflammasome assembly, caspase-1 activation, histological changes, and liver enzyme levels were measured. Statistical comparison of more than two groups was performed using one-way ANOVA with Tukey's post-hoc testing. The correlations were analyzed using Pearson's correlation test. All experiments were repeated thrice. A p-value < 0.05 was considered significant. RESULTS: Heat stroke induced histone release into the extracellular space at levels correlating with liver injury. Moreover, extracellular histones augmented heat stroke-induced liver injury both in vitro and in vivo in a dose- and time-dependent manner, whereas neutralizing histones conferred protection following heat stroke. Histones mediated NOD-like receptor family pyrin domain-containing 3 inflammasome activation through the Toll-like receptor 9 signaling pathway, which resulted in hepatocyte pyroptosis and liver inflammation. CONCLUSIONS: Our findings show that histones are critical mediators of hepatocyte pyroptosis that aggravate liver injury in a heat stroke setting. Therefore, we suggest extracellular histones as potential therapeutic targets to limit heat stroke-induced cell death and liver injury.

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.

[Analysis of clinical characteristics and risk factors of early heat stroke-related acute liver injury].

OBJECTIVE: To analyze the clinical characteristics and risk factors of early acute liver injury in patients with heat stroke (HS), and to provide basis for early identification of HS-related liver injury and its pathogenesis in clinical practice. METHODS: The clinical data of patients with HS admitted to the department of critical care medicine of Haian People's Hospital from June 2015 to August 2022 were retrospectively analyzed. The patients with HS were divided into early liver injury group and early non-liver injury group according to the occurrence of acute liver injury within 24 hours of admission. The differences of basic data, clinical data, laboratory indexes and clinical outcomes of the two groups were analyzed. Logistic regression was used to analyze the risk factors for early HS-related acute liver injury, and receiver operator characteristic (ROC) curves were drawn to evaluate their value in predicting the occurrence of early HS-related acute liver injury. RESULTS: A total of 76 patients with HS were enrolled, and 46 patients with acute liver injury, accounting for 60.53%. In the early liver injury group, 14 patients (30.43%) had elevated aminotransferase alone, 9 patients (19.57%) had elevated total bilirubin (TBil) alone, and 23 patients (50.00%) had elevated both aminotransferase and TBil. Among the patients with elevated aminotransferases, 24 patients (64.87%) had mild elevation, 5 patients (13.51%) had moderate elevation, 8 patients (21.62%) had severe elevation. Compared with the early non-liver injury group, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), arterial blood lactate (Lac), interleukin-6 (IL-6), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBil, γ-gamma glutamyl transferase (γ-GGT), lactate dehydrogenase (LDH), creatine kinase (CK), MB isoenzyme of creatine kinase (CK-MB), cardiac troponin I (cTnI), myoglobin (MYO), N-terminal B-type pro-brain natriuretic peptide (NT-proBNP), prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer in the early liver injury group were significantly increased, while platelet count (PLT) were significantly decreased within 24 hours after admission, the 28-day mortality was significantly increased [28.26% (13/46) vs. 6.67% (2/30)], and the differences were statistically significant (all P < 0.05). Univariate Logistic regression analysis showed that APACHE II score, SOFA score, PLT, Lac, IL-6, PCT, γ-GGT, LDH, CK, CK-MB, cTnI, MYO, PT, APTT, D-dimer were risk factors of early HS-related acute liver injury (all P < 0.05). Multivariate Logistic regression analysis showed that PLT, IL-6, and LDH were independent risk factors of early HS-related acute liver injury [odds ratio (OR) and 95% confidence interval (95%CI) were 0.986 (0.974-0.998), 1.027 (1.012-1.041), and 1.002 (1.000-1.004), all P < 0.05]. The ROC curve analysis showed that the area under the ROC curve (AUC) of PLT, IL-6 and LDH for predicting the occurrence of early HS-related acute liver injury was 0.672 (95%CI was 0.548-0.797), 0.897 (95%CI was 0.824-0.971) and 0.833 (95%CI was 0.739-0.927), respectively. IL-6 had the highest predictive value for early HS-related liver injury. When the optimal diagnostic threshold of IL-6 was 48.25 ng/L, the sensitivity was 95.7%, the specificity was 73.3%, and the predictive value of PLT was the lowest. CONCLUSIONS: The early HS-related liver injury is mainly manifested as the simultaneous elevation of aminotransferase and TBil, and most of cases are mild liver injury. PLT, IL-6 and LDH are independent risk factors of early HS-related acute liver injury.

Inhibition of the MLCK/MLC2 pathway protects against intestinal heat stroke-induced injury in rats.

Intestinal barrier dysfunction often exists in the heat stroke (HS) pathological process, which increases intestinal permeability and induces endotoxemia. The upregulation of MLCK is a crucial player affecting intestinal permeability. This study aimed to explore whether inhibiting myosin light chain kinase (MLCK) can improve HS-induced intestinal injury in rats. Twelve-week-old Wistar male rats were divided into three groups: the control group, the HS model group, and the treatment group [HS model + ML-7 (MLCK inhibitor)]. HS impaired the tight junctions in the rat gut and increased permeability. Additionally, increased inflammatory factors in serum, activation of apoptosis, and downregulation of tight junction proteins were observed in intestinal cells. ML-7 significantly inhibited the MLCK/p-MLC2 signaling pathway, increased the expression of tight junction proteins, reduced intestinal permeability, reduced apoptosis and alleviated the intestinal damage caused by HS. ML-7 inhibited HS-induced apoptosis of intestinal epithelial cells by regulating the ERK/p38/HSP70 axis. Furthermore, inhibition of MLCK upregulated HSP70 expression through activation of the ERK pathway and inhibited cell apoptosis by abolishing the p38 MAPK pathway. In conclusion, inhibiting the MLCK/p-MLC2 signaling pathway reduces HS-induced intestinal permeability and protects the intestinal mucosal barrier.

Secondary hemophagocytic lymphohistiocytosis associated with heat stroke: A case report and review of literature.

RATIONALE: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome with potentially fatal consequences that results from an excessive immune response caused by malfunctioning natural killer cells and cytotoxic T lymphocytes. Secondary HLH, which is the predominant type in adults, is associated with various medical conditions, including infections, malignancies, and autoimmune diseases. Secondary HLH associated with heat stroke has not been reported. PATIENT CONCERNS: A 74-year-old male was admitted to the emergency department after being unconscious in a 42°C hot public bath. The patient was witnessed to be in the water for more than 4 hours. The patient's condition was complicated by rhabdomyolysis and septic shock, which were managed with mechanical ventilation, vasoactive agents, and continuous renal replacement therapy. The patient also showed evidence of diffuse cerebral dysfunction. DIAGNOSES: While the patient's condition initially improved, the patient developed a fever, anemia, thrombocytopenia, and an acute rise in total bilirubin, which, we suspected, was caused by HLH. Further investigations revealed elevated serum ferritin and soluble interleukin-2 receptor levels. INTERVENTIONS: The patient received 2 cycles of serial therapeutic plasma exchange to lower the endotoxin burden. To manage HLH, high-dose glucocorticoid therapy was done. OUTCOMES: Despite the best efforts, the patient did not recover and expired from progressive hepatic failure. LESSONS: We report a novel case of secondary HLH associated with heat stroke. Diagnosing secondary HLH can be difficult since clinical manifestations of the underlying disease and HLH may present simultaneously. Early diagnosis and prompt initiation of treatment is required to improve the prognosis of the disease.

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.

Bovine Lactoferrin Alleviates Pulmonary Lipid Peroxidation and Inflammatory Damage in Heat Stroke Rats.

Lung injury occurring in the early stage of heat stroke (HS) leads to hypoxia and further aggravation of other organic damage. Lactoferrin (LF) is an iron binding protein with anti-inflammatory and antioxidant effects. This study focuses on the protection of preadministration of bovine lactoferrin (BLF) against lung injury in rats with HS. Sixty-four Sprague-Dawley male rats were divided into four groups randomly: control (CON)+phosphate-buffered saline (PBS) (n = 16), HS+PBS (n = 16), HS+low-dose BLF (LBLF) (n = 16), and HS+high-dose BLF (HBLF) (n = 16). CON+PBS and HS+PBS were preadministered 10 mL/kg PBS for 1 week. HS+LBLF and HS+HBLF were preadministered 100 and 200 mg/kg BLF for 1 week, respectively. The HS onset time and the survival rate were recorded, and bronchoalveolar lavage fluid was obtained to measure protein concentration. Lung was obtained for pathological analysis and wet/dry weight ratio measurement; later, the content of malondialdehyde (MDA), activity of myeloperoxidase (MPO), and superoxide dismutase (SOD) were measured in lung tissue homogenate. The results indicated that BLF preadministration could delay the HS onset time, enhance the survival rate, the levels of serum inflammatory cytokine and MDA content in HS+LBLF and HS+HBLF showed significant reduction compared with HS+PBS, while a significant elevation of SOD activity and reduction of MPO activity in HS+HBLF. Our results demonstrate that BLF preadministration could relieve lung injury in HS rats by enhancing thermal endurance, and alleviating serum inflammatory response and pulmonary oxidative stress damage.

Anti-Inflammatory and Anti-Oxidative Effects of Isorhamnetin for Protection Against Lung Injury in a Rat Model of Heatstroke in a Dry-Heat Environment.

BACKGROUND Isorhamnetin is a natural flavonoid compound with anti-inflammatory and antioxidant properties. However, its roles in alleviating lung injury associated with heatstroke remain unclear. Therefore, this study aimed to evaluate the protective effects of different isorhamnetin doses on lung injury in heatstroke rat models exposed to a dry-heat environment. MATERIAL AND METHODS Fifty Sprague-Dawley rats were randomly divided into 5 groups: normal control (0.9% saline), heatstroke (0.5% CMCNa), and isorhamnetin (25, 50, and 100 mg/kg) groups; treatments were administered by gavage daily for 7 days. All rats, except those in the control group, were exposed to a dry-heat environment (41±1°C, 10±2% relative humidity) for 150 min to induce heatstroke. Pathological changes, ultrastructure, edema, inflammation, and oxidative stress in the lungs were assessed. RESULTS Compared with the heatstroke group, rats treated with 100 mg/kg isorhamnetin showed amelioration of histopathological and ultrastructural changes in the lungs; decreased lung injury scores (P<0.05) and wet/dry weight ratios (P<0.01); lower levels of phospho-nuclear factor-kappaB (P<0.05), high-mobility group box 1 (P<0.01), tumor necrosis factor-alpha (P<0.01), interleukin (IL)-1ß (P<0.01), and IL-6 (P<0.01); lower malondialdehyde contents (P<0.01); and higher superoxide dismutase (P<0.01) and catalase activities (P<0.05). CONCLUSIONS In a dry-heat environment, isorhamnetin protected against lung injury in heatstroke rat models via anti-inflammatory and anti-oxidative mechanisms.

Thromboelastography maximum amplitude as an early predictor of disseminated intravascular coagulation in patients with heatstroke.

OBJECTIVES: The aim of this study was to investigate the ability of TEG to predict DIC associated with heatstroke. METHODS: We carried out a retrospective, single-center study of 67 patients with heatstroke admitted to an intensive care unit (ICU) at a comprehensive hospital between July 2016 and August 2021. Conventional coagulation tests (CCTs) and TEG were performed within 2 h of admission in ICU. Patients were diagnosed with DIC based on International Society of Thrombosis and Hemostasis criteria, and those with or without DIC were compared in terms of CCTs and TEG findings. The ability of individual parameters to predict DIC was assessed based on logistic regression and the area under receiver operating characteristic curves (AUC). RESULTS: Of the 67 patients, 19 (28.4%) were diagnosed with DIC. Compared to patients without DIC, those with DIC had significantly longer reaction time [14.5(10.6-26.0) vs. 6.2(5.1-10.1)min](p < 0.001) and kinetic time [10.9(5.9-25.0) vs. 2.7(2.2-4.7) min](p < 0.001). Conversely, those with DIC had significantly lower alpha angle [22(9.1-43.3) vs. 55.0(44.8-61.7)°](p < 0.001), maximum amplitude (MA) [(26.9(17.7-41.4) vs. 52.2(45.8-58.1) mm)] (p < 0.001) and coagulation index [-17.3(-39 to -7.9）vs. -2.4(-6.2to-0.6)](p < 0.001). MA at a cutoff value of 45.4 mm gave an AUC of 0.9 for predicting DIC, with sensitivity of 77.1%, specificity of 89.5%, positive predictive value of 10.5% and negative predictive value of 22.9%. Multifactorial logistic regression identified MA < 45.4 mm as an independent predictor of DIC (odds ratio 9, 95% confidence interval 1.2-69.2, p = 0.035). MA decreased significantly as DIC score increased and was significantly lower in the non-survivors on admission. CONCLUSIONS: MA < 45.4 mm in patients with heatstroke may predict elevated risk of DIC. HighlightsPatients with heatstroke-induced disseminated intravascular coagulation (DIC) has high mortality.A retrospective, single-center study was performed to investigate the ability of thromboelastography (TEG) to predict DIC associated with heatstroke.The maximum amplitude (MA) value of TEG decreased significantly with the increase of DIC score.MA < 45.4 mm was firstly demonstrated to an independent predictor of heatstroke-induced DIC.

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.

Heat Stroke as a Cause of Liver Failure and Evaluation of Liver Transplant.

Heat stroke is a multiple organ dysfunction syndrome of poorly understood pathogenesis. Exertional heat stroke with acute liver failure is a rarely reported condition. Liver transplant has been recommended as treatment in cases of severe liver dysfunction; however, there are only 5 described cases of long-term survival after this procedure in patients with heat stroke. Here, we present 2 cases of young athletes who developed heat stroke. Both patients developed acute liver failure and were listed for liver transplant. Liver function tests of one patient improved, and he was discharged on postoperative day 13. The other patient showed no signs of improvement and liver biopsy showed massive necrosis. The patient underwent combined kidney-liver transplant and was discharged on postoperative day 17. After a follow-up of longer than 6 years, both patients are doing well with normal liver function and no neurologic sequelae. We also reviewed all published cases of hepatic failure associated with heat stroke and found 9 published cases of liver transplant for heat stroke in the English literature. Conservative management appears to be justified in heat stroke-associated liver failure, even in the presence of accepted criteria for emergency liver transplant. If the liver does not show signs of recovery and hepatic decompensation progresses, liver transplant should be performed.

[Hydroxysafflor yellow A attenuates heat stroke-induced acute lung injury in mice by inhibiting necroptosis].

OBJECTIVE: To investigate the protective effect of hydroxysafflor yellow A (HSYA) against heat stroke (HS)-induced acute lung injury and its possible mechanism. METHODS: The optimal dose of HSYA pretreatment via intraperitoneal injection prior to HS was determined in a mice by observing heat tolerance of the mice. C57BL/6J mice were pretreated with HSYA at the optimal dose or with Nec-1 (a RIP1 activation inhibitor) before HS, and the changes in core body temperature and survival of the mice were observed during the 72-h recovery period. At different stages of recovery, lung tissues, bronchoalveolar lavage fluid and blood samples were collected from the mice for assessing lung tissue pathology, wet-to-dry weight ratio and water content of the lungs; leukocyte and neutrophil counts, total protein levels and HMGB1 level in the bronchoalveolar lavage fluid (BLF) were also detected. Serum levels of TNF-α, IL-6 and HMGB1 were detected with ELISA, and the expression levels of RIP1, RIP3, MLKL-s358, MLKL and MLKL-s358 proteins in the lung tissues were detected using Western blotting. RESULTS: HSYA pretreatment at the moderate and high doses significantly improved heat tolerance of the mice with comparable effects. At the optimal dose of 2.25 mg/kg, HSYA pretreatment significantly increased heat tolerance of the mice (P<0.05), showing a similar effect with Nec-1 pretreatment. Pretreatment with HSYA and Nec-1 both significantly increased survival rate of the mice (P<0.05), lowered histopathological score and water content of the lungs, and reduced the levels of TNF-α, IL-6 and HMGB1 (P<0.05), leukocyte and neutrophil counts, and total protein and HMGB1 levels in the BLF (P<0.05). The mice during recovery from HS showed significantly increased RIP1 expression and MLKL-s358 phosphorylation level in the lung tissue (P<0.05), which were obviously lowered by HSYA pretreatment of the mice. CONCLUSION: Severe HS results in necroptosis in the lung tissue of mice, which can be alleviated by HSYA pretreatment.

Bone Scanning Findings in a Patient with Heat Stroke-Induced Rhabdomyolysis.

We present a case that caused a diagnostic dilemma on a bone scan. We also review the broad spectrum of nonmalignant findings that can impact the interpretation of a bone scan and the value of correlative imaging using SPECT/CT for exact localization and characterization of lesions. The imaging features of important benign pathologies-that is, metastatic mimics-are elaborated so that the reader can avoid misinterpretations when reporting them. We elucidate 4 uncommon benign findings on a bone scan. Rhabdomyolysis is a result of lysis of skeletal muscle with release of cell contents, such as myoglobin and muscle enzymes, and is diagnosed mostly through a combination of clinical appearance and laboratory values. Myositis ossificans is the most common form of heterotopic ossification, usually occurring within large muscles. Its importance stems largely from its ability to mimic more aggressive pathologic processes. Myositis ossificans is one of the skeletal "do not touch" lesions. Such bone lesions are defined by characteristic imaging features, the identification of which precludes the need for additional diagnostic tests or biopsies, thereby avoiding unnecessary interventions. Acute tubular necrosis is kidney injury caused by damage to the kidney tubule cells (kidney cells that reabsorb fluid and minerals from urine as it forms). Common causes are low blood flow to the kidneys, drugs that damage the kidneys, or a severe underlying infection.

Clinical characteristics and risk factors of male exertional heatstroke in patients with myocardial injury: an over 10-year retrospective cohort study.

BACKGROUND: Heatstrokes are a serious threat to human health, particularly the cardiovascular system. Understanding the clinical features and risk factors related to death in patients with myocardial injury (MI) complicated by heat stroke is crucial. METHOD: This study included the baseline data of all patients with severe heatstroke between October 2008 and May 2019. RESULTS: Of the 162 patients enrolled, 75 (46.3%) were in the MI group and 87 (53.7%) were in the non-MI group. A significant difference was noted in 90-day survival between the two groups even after correction for Age, Acute Physiology, and Chronic Health Evaluation II (APACHE II) scores, Sequential Organ Failure Assessment (SOFA) scores, Glasgow Coma Score (GCS), and activated partial thromboplastin time (before correction (p < .001; after correction, p = .023). Survival analysis showed that the 90-day survival time of patients with MI was shorter than that of patients without MI (p < .001). The area under the receiver operating characteristic (ROC) curve for predicting mortality based on the SOFA score was 92.8% (95% CI 0.847-1.000, p < .001), the optimal cutoff value was 7.5, the sensitivity was 91.7%, and the specificity was 94.6%. CONCLUSION: Patients with heatstroke having MI had more severe clinical conditions, 90-day mortality was significantly increased, and the survival time was shortened. A high SOFA score is an independent risk factor for death in patients with heatstroke having MI, with an optimal cutoff value of 7.5, sensitivity of 91.7%, and specificity of 94.6%.

Exertional heat stroke in an amateur runner - Challenges in diagnostics and the role of unhealthy competition.

Exertional heat stroke (EHS) is a potentially life-threatening condition with a variety of symptoms and abnormal laboratory findings. Nevertheless, data evaluating the course of making an EHS diagnosis in real-life practice, as well as the role of predisposing psychological components are limited. Thus, the aim of our study was to present a multi-faceted differentiation process and show the role of unhealthy competition in the development of EHS. We describe a case of a young amateur runner, admitted to the hospital due to loss of consciousness, further mental confusion, and increased body temperature above 40°C. Head scans excluded brain haemorrhage and stroke. Elevated troponin I levels suggested an acute coronary syndrome (ACS) or myocarditis. An increase of procalcitonin levels, signs of rhabdomyolysis and severe liver injury resulted in evaluation for infection and acute hepatic damage. Subsequently, the patient's negative results pointed us to a diagnosis of EHS. In-depth anamnesis revealed that the patient's excessive effort during the race was linked to the male-female competition. EHS can present diagnostic challenges, as it mimics various diseases, such as stroke, myocarditis, ACS, infection, or liver dysfunction. In addition, the role of psychological components, such as unhealthy competition, in the development of EHS should be considered.

Impact of rhabdomyolysis on outcomes of hospitalizations for heat stroke in the United States.

BACKGROUND: The objective of this study was to evaluate the predictors and associated outcomes of rhabdomyolysis in admitted patients for heat stroke in the United States. METHODS: The National Inpatient Sample was utilized to identify hospitalized patients with a primary diagnosis of heat stroke from the years 2003-2014. Rhabdomyolysis was identified using hospital diagnosis code. We compared the clinical characteristics, in-hospital treatment, complications, outcomes, and resource utilization between patients with and without rhabdomyolysis. RESULTS: A total of 3,372 hospital admissions for heat stroke were studied. Of these, rhabdomyolysis occurred in 1049 (31%) admissions. The risk factors for rhabdomyolysis were age 20-39 years, male sex, African American race, history of alcohol drinking, whereas age ≥60 years, smoking, history of diabetes mellitus, and hypertension were associated with lower risk of rhabdomyolysis. Patients with rhabdomyolysis had greater requirements for mechanical ventilation, blood component transfusion, and renal replacement therapy. Rhabdomyolysis was significantly associated with increased risk of hyponatremia, hypernatremia, hyperkalemia, hypocalcemia, serum phosphorus and magnesium derangement, metabolic acidosis, sepsis, ventricular arrhythmia or cardiac arrest, renal failure, respiratory failure, liver failure, neurological failure, hematologic failure, and in-hospital mortality. Length of hospital stay and hospitalization cost were higher when rhabdomyolysis occurred during hospital stay. CONCLUSION: Rhabdomyolysis occurred in about one-third of hospitalized patients for heat stroke and was associated with increased morbidity, mortality, and resource utilization.

Preventing necroptosis by scavenging ROS production alleviates heat stress-induced intestinal injury.

Background: Worldwide heat stroke incidence has increased in recent years and is associated with high morbidity and mortality. Therefore, it is critical to identify mechanisms that mediate heat stroke. Previous studies suggested that damage to the small intestine may be a major factor in heat stroke-related morbidity and mortality. However, the mechanism underlying heat stroke related small intestine injury remains unclear.Methods: To explore how heat stroke promotes intestinal damage, we applied two well established models: mouse and IEC-6 cells heat stress (HS) to mimic heat stroke both in vivo and in vitro. The percentages of viability and cell death were assessed by WST-1 and LDH release assays. Induction of HS-induced cell death was analyzed by flow cytometry with Annexin V-FITC/PI staining. Flow cytometry was used to analyze HS-induced mitochondrial superoxide with MitoSOX staining. Malondialdehyde (MDA) levels and superoxide dismutase (SOD) levels were detected by ELISA. Flow cytometry was used to analyze HS-induced mitochondrial depolarization (low ΔΨm) with JC-1 staining. Histopathology changes in the ileum were detected by H&E staining.The ileum ultrastructure was observed by transmission electron microscopy (TEM). RIPK1, RIPK3, phosphorylated MLKL, and MLKL levels were detected by Western blot. RIPK1-RIPK3 complexes were measured by immunoprecipitation assay.Results: HS increased both necrotic cell rate and RIPK1, RIPK3, and phosphorylated MLKL expression levels in IEC-6 cells. These increased expression levels promoted higher RIPK1-RIPK3 complex formation, leading to necrosome formation both in vivo and in vitro. Moreover, HS caused dyshomeostasis, an oxidative stress response, and mitochondrial damage, along with small intestinal tissue injury and cell death. However, IEC-6 cells or mice pretreated with the RIPK1 activity chemical inhibitor Nec-1 or RIPK3 activity chemical inhibitor GSK'872 significantly reversed these phenomena and promoted balance in oxidative stress response homeostasis. More importantly, the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) pretreatment significantly inhibited HS-induced RIPK1/RIPK3-dependent necroptosis formation both in vivo and in vitro, suggesting that preventing necroptosis via scavenging ROS production might alleviate HS-induced small intestinal tissue injury and cell death.Conclusion: This study provides strong evidence that HS causes damage to both the small intestine and intestinal epithelial cells, scavenging ROS production can significantly alleviate such RIPK1/RIPK3-dependent necroptosis, mediating HS-induced intestinal damage both in vitro and in vivo. These findings provide a clear target for future mechanism-based therapeutic strategies for patients diagnosed with heat stroke.

A knack for "NAC": Treatment for heat stroke induced acute liver injury.

INTRODUCTION: Heat stroke occurs when the body's core temperature becomes elevated above 40 °C, which may impact multiple organ systems. We present a case of heat stroke resulting in acute liver injury (ALI) successfully treated with intravenous N-acetylcysteine (NAC). CASE PRESENTATION: A 24-year-old unresponsive male without significant past medical history presented to the emergency department with heat stroke; his initial temperature was 107.4 °F. During his hospital course, he developed ALI with significant elevation in aspartate aminotransferase, alanine aminotransferase, and total bilirubin. These laboratory findings peaked by hospital day two, but improved prior to discharge on hospital day five and throughout his follow up clinic visits. His treatment course included cooling measures, supportive care, supplemental oxygen and airway management, seizure control, and intravenous NAC therapy. CONCLUSION: Hepatocellular injury is one of the most serious complications of heat stroke. We discuss the incidence and outcomes for patients who develop acute liver injury secondary to heat stroke and the use of NAC as an early potential therapeutic option.