Prior viral illness increases heat stroke severity in mice.

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

The prognostic value of routine coagulation tests for patients with heat stroke.

OBJECTIVE: To evaluate the prognostic value of routine coagulation tests for patients with heat stroke. METHODS: This was a multi-center retrospective study. Patients who arrived at the hospital <24 h after the onset of Heat Stroke (HS) were included. The routine coagulation variables were detected within 24 h after the onset, including the lowest platelet count (PLC). RESULTS: 60-day mortality rate was 20.9%. The median Prothrombin Time-International Normalized Ratio (PT-INR) of the non-surviving patients was significantly higher than that of the survivors (P < 0.01). The median Activated Partial Thromboplastin Time (APTT) in non-surviving patients was significantly higher than in the surviving patients (P < 0.01). A Cox regression analysis revealed that 60-day mortality was associated with PT-INR (P = 0.032) and APTT (P = 0.004). The optimal PT-INR point for predicting 60-day mortality rate was 1.7. The optimal APTT point for predicting 60-day mortality was 51.45. Patients with increased PT-INR (≥1.7) levels had, overall, a significantly reduced survival time (P < 0.01). Patients with elevated APTT (≥51.45) also had a decrease in survival time (P < 0.01). The prognostic scoring, with increased PT-INR (≥1.7) and prolonged APTT (≥51.45) at one point each, was also demonstrated to be useful in predicting 60-day mortality. Patients whose temperature fell to 38.9 °C within 30 min had significantly lower levels of PT-INR and APTT within 24 h than those who took longer to cool down. CONCLUSIONS: A prolonged APTT and elevated PT-INR within 24 h are independent prognostic factors of 60-day mortality in HS.

The Role of Skeletal Muscles in Exertional Heat Stroke Pathophysiology.

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

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.

Electrolyte disturbances and risk factors of acute kidney injury patients receiving dialysis in exertional heat stroke.

BACKGROUND: Exertional heat stroke (EHS) is a life-threatening illness and leads to multi-organ dysfunction including acute kidney injury (AKI). The clinical significance of abnormal electrolytes and renal outcomes in ESH patients has been poorly documented. We aim to exhibit the electrolyte abnormalities, renal outcomes and risk factors of patients with AKI receiving dialysis in EHS. METHODS: A retrospective cohort study in EHS patients between 2003 and 2014 were conducted. Clinical and laboratory outcomes including serum and urine electrolytes, AKI and dialysis were assessed on admission, during hospitalization and at the time of their discharge from the hospital. A logistic regression analysis was performed for risk factors of acute dialysis. RESULTS: All 66 subjects with mean age 22.1 ± 4.3 years were included. On admission, the common electrolyte disturbances were hypokalemia (71.2 %), hypophosphatemia (59.1 %), hyponatremia (53.0 %), hypocalcemia (51.5 %), and hypomagnesemia (34.9 %). Electrolytes depletion was confirmed as renal loss (potassium loss; 54.2 %, phosphate loss; 86.7 %, sodium loss; 64.7 % and magnesium loss; 83.3 %). During hospitalization ranging from 2 to 209 days, 90.9 % patients suffered from AKI with 16.7 % receiving acute dialysis, and 3 % patients died. At discharge, AKI and electrolyte abnormalities had dramatically improved. The prognosis factors for AKI receiving dialysis were identified as neurological status, renal function and serum muscle enzyme at time of admission. CONCLUSION: The study suggests that hypoelectrolytemia and AKI are frequently observed in patients with EHS. Neurological impairment, impaired renal function, and increased serum muscle enzyme should be considered risk factors of acute dialysis.

Point-of-care cardiac troponin test accurately predicts heat stroke severity in rats.

Heat stroke (HS) remains a significant public health concern. Despite the substantial threat posed by HS, there is still no field or clinical test of HS severity. We suggested previously that circulating cardiac troponin (cTnI) could serve as a robust biomarker of HS severity after heating. In the present study, we hypothesized that (cTnI) point-of-care test (ctPOC) could be used to predict severity and organ damage at the onset of HS. Conscious male Fischer 344 rats (n = 16) continuously monitored for heart rate (HR), blood pressure (BP), and core temperature (Tc) (radiotelemetry) were heated to maximum Tc (Tc,Max) of 41.9 ± 0.1°C and recovered undisturbed for 24 h at an ambient temperature of 20°C. Blood samples were taken at Tc,Max and 24 h after heat via submandibular bleed and analyzed on ctPOC test. POC cTnI band intensity was ranked using a simple four-point scale via two blinded observers and compared with cTnI levels measured by a clinical blood analyzer. Blood was also analyzed for biomarkers of systemic organ damage. HS severity, as previously defined using HR, BP, and recovery Tc profile during heat exposure, correlated strongly with cTnI (R(2) = 0.69) at Tc,Max. POC cTnI band intensity ranking accurately predicted cTnI levels (R(2) = 0.64) and HS severity (R(2) = 0.83). Five markers of systemic organ damage also correlated with ctPOC score (albumin, alanine aminotransferase, blood urea nitrogen, cholesterol, and total bilirubin; R(2) > 0.4). This suggests that cTnI POC tests can accurately determine HS severity and could serve as simple, portable, cost-effective HS field tests.

Association of plasma diamine oxidase and intestinal fatty acid-binding protein with severity of disease in patient with heat stroke.

OBJECTIVES: The aim of this study was to describe the role of intestinal fatty acid-binding protein (iFABP) and allergy-related diamine oxidase (DAO) in patients with heat stroke (HS). METHODS: A total of 10 patients with HS in intensive care unit and 10 healthy volunteers were enrolled in this study. The plasma intestinal permeability markers iFABP and DAO were measured since the time of admission. The whole blood endotoxin was also assessed. The associations between iFABP, DAO, and endotoxin level were analyzed. Then, white blood cell count, procalcitonin, and C-reactive protein were examined. In addition, we also determined the levels of proinflammatory cytokines such as IL-1α, IL-6, and TNF-α. RESULTS: Comparing with the healthy control, the plasma iFABP and DAO level in patients with HS increased significantly (P < .05). The kinetic curve showed that plasma iFABP and DAO level reached peak value at day 3 and day 4 after admission, respectively. The endotoxin level was positively correlated with iFABP and DAO level. We also observed a significantly increased level of procalcitonin and C-reactive protein but not white blood count in patients with HS. After treatment, the iFABP and DAO level decreased significantly (P < .05). A significant increase in level of IL-1α and IL-6 was also found in patients with HS. CONCLUSIONS: The plasma concentrations of DAO and iFABP could reflect a better function of the intestinal mucosa barrier in patients with HS. Plasma iFABP and DAO level decreased significantly after the treatment and, thus, might be a predictor for the severity of HS.

Xuebijing injection reduces organ injuries and improves survival by attenuating inflammatory responses and endothelial injury in heatstroke mice.

BACKGROUND: The pathogenesis of heatstroke is a multi-factorial process involved with an interplay among subsequent inflammation, endothelial injury and coagulation disturbances, which makes pharmacological therapy of heatstroke a challenging problem. Xuebijing injection (XBJ), a traditional Chinese medicine used to sepsis, has been reported to suppress inflammatory responses and restore coagulation disturbances. However, little is known about the role of XBJ in heatstroke. METHODS: Mice were treated with indicated dose of XBJ before and/or after the induction of heatstroke. Serum inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and endothelial markers, von Willebrand Factor (vWF) and E-selectin, were measured by ELISA. Liver, kidney and heart profiles including alanine aminotransferase, aspartic aminotransferase, creatinine, blood urea nitrogen, and lactate dehydrogenase, were evaluated by UniCel DxC 800 Synchron Clinical Systems, and troponin was measured by ELISA. Coagulation profiles, including thrombin time, prothrombin time, activated partial thromboplastin time, international normalized ratio, and fibrinogen were examined by STA Compact® Hemostasis System. Jejunum injury was evaluated with H&E staining. Changes in mitochondrial structure in cardiac tissue were assesed by electron microscopy. RESULTS: Pretreatment with XBJ decreased serum pro-inflammatory cytokines including TNF-α and IL-6, as well as endothelial injury markers, vWF and E-selectin, in a dose-dependent manner in heatstroke mice. Similar protective effects were observed when XBJ was administered after, or both before and after heat insult. These protective effects lasted for over 12 h in mice receiving XBJ before and after heat insult. XBJ also improved survival rates in heatstroke mice, ameliorated liver, heart, and kidney injuries, including mitochondrial damage to the heart, and reduced coagulation disturbances. CONCLUSIONS: XBJ prevents organ injuries and improves survival in heatstroke mice by attenuating inflammatory responses and endothelial injury. XBJ may be a potentially useful in the prevention and treatment of heatstroke.

Plasma and lymphocyte Hsp72 responses to exercise in athletes with prior exertional heat illness.

We investigated the effect of exercise in the heat on both intracellular and extracellular Hsp72 in athletes with a prior history of exertional heat illness (EHI). Two groups of runners, one consisting of athletes who had a previous history of EHI, and a control group (CON) of similar age (29.7 ± 1.2 and 29.1 ± 2 years CON vs. EHI) and fitness [maximal oxygen consumption [Formula: see text] 65.7 ± 2 and 64.5 ± 3 ml kg(-1) min(-1) CON vs. EHI] were recruited. Seven subjects in each group ran on a treadmill for 1 h at 72 % [Formula: see text] in warm conditions (30 °C, 40 % RH) reaching rectal temperatures of ~39.3 (CON) and ~39.2 °C (EHI). Blood was collected every 10 min during exercise and plasma was analysed for extracellular Hsp72. Intracellular Hsp72 levels were measured in both monocytes and lymphocytes before and immediately after the 60-min run, and then after 1 h recovery at an ambient temperature of 24 °C. Plasma Hsp72 increased from 1.18 ± 0.14 and 0.86 ± 0.08 ng/ml (CON vs. EHI) at rest to 4.56 ± 0.63 and 4.04 ± 0.45 ng/ml (CON vs. EHI, respectively) at the end of exercise (p < 0.001), with no difference between groups. Lymphocyte Hsp72 was lower in the EHI group at 60 min of exercise (p < 0.05), while monocyte Hsp72 was not different between groups. The results of the present study suggest that the plasma Hsp72 response to exercise in athletes with a prior history of EHI remained similar to that of the CON group, while the lymphocyte Hsp72 response was reduced.

Heatstroke model for desert dry-heat environment and observed organ damage.

BACKGROUND: Heatstroke is one of the most common clinical emergencies. Heatstroke that occurred in a dry-heat environment such as desert is usually more seriously effective and often leads to death. However, the report of the pathophysiologic mechanisms about heatstroke in dry-heat environment of desert has not been seen. OBJECTIVES: Our objectives are to establish a rat model of heatstroke of dry-heat environment of desert, to assess the different degrees of damage of organ, and to preliminarily discuss the mechanism of heatstroke in dry-heat environment of desert. METHODS: The first step, we have established a rat heatstroke model of dry heat environment of desert. The second step, we have accessed changes in morphology and blood indicators of heatstroke rats in dry-heat environment of desert. RESULTS: The heatstroke rats have expressed the changing characteristics of mean arterial pressure, core temperature, and heart rate. The organ damage changed from mild to serious level, specifically in the morphology and blood enzymology parameters such as alanine aminotransferase, aspartate aminotransferase, creatinine, urea, uric acid, creatine kinase-MB, creatine kinase, and blood gas parameters such as base excess extracellular fluid and bicarbonate ions (HCO3-). CONCLUSIONS: We have successfully established the rat heatstroke model of dry-heat environment of desert. We have identified heatstroke rats that presented changing characteristics on physiological indicators and varying degrees of organ damage, which are aggravated by the evolution of heatstroke in dry-heat environment of desert. We have preliminarily discussed the mechanism of heatstroke in dry-heat environment of desert.

Thromboelastometry for assessment of hemostasis and disease severity in 42 dogs with naturally-occurring heatstroke.

BACKGROUND: Thromboelastometry (TEM) provides a comprehensive overview of the entire coagulation process and has not been evaluated in heatstroke-induced coagulopathies in dogs. OBJECTIVES: To determine the diagnostic and prognostic utility of TEM in dogs with heatstroke. ANIMALS: Forty-two client-owned dogs with heatstroke. METHODS: Prospective observational study. Blood samples for intrinsic and extrinsic TEM (INTEM and EXTEM, respectively) were collected at presentation and every 12 to 24 hours for 48 hours. Coagulation phenotype (hypo-, normo-, or hypercoagulable) was defined based on TEM area under the 1st derivative curve (AUC). RESULTS: Case fatality rate was 31%. Median TEM variables associated with death (P < .05 for all) included longer INTEM clotting time, lower AUC at presentation and at 12 to 24 hours postpresentation (PP), lower INTEM alpha angle, maximum clot firmness, and maximum lysis (ML) at 12 to 24 hours PP, and lower EXTEM ML at 12 to 24 hours PP. Most dogs were normo-coagulable on presentation (66% and 63% on EXTEM and INTEM, respectively), but hypo-coagulable 12 to 24 PP (63% for both EXTEM and INTEM). A hypo-coagulable INTEM phenotype was more frequent at presentation and 12 to 24 PP among nonsurvivors compared to survivors (55% vs 15% and 100% vs 50%, P = .045 and .026, respectively). AKI was more frequent (P = .015) in dogs with hypo-coagulable INTEM tracings at 12 to 24 hours. Disseminated intravascular coagulation was more frequent (P < .05) in dogs with a hypo-coagulable INTEM phenotype and in nonsurvivors at all timepoints. CONCLUSIONS AND CLINICAL RELEVANCE: Hypocoagulability, based on INTEM AUC, is predictive of worse prognosis and occurrence of secondary complications.

Hyperthermia and postmortem biochemical investigations.

The postmortem diagnosis of heat-related deaths presents certain difficulties. Firstly, preterminal or terminal body temperatures are often not available. Additionally, macroscopic and microscopic findings are nonspecific or inconclusive and depend on survival duration after exposure. The diagnosis of hyperthermia is therefore essentially based on scene investigation, the circumstances of death, and the reasonable exclusion of other causes of death. Immunohistochemistry and postmortem biochemical investigations have been performed by several authors in order to better circumstantiate the physiopathology of hyperthermia and provide further information to confirm or exclude a heat-related cause of death. Biochemical markers, such as electrolytes, hormones, blood proteins, enzymes, and neurotransmitters, have been analyzed in blood and other biological fluids to improve the diagnostic potential of autopsy, histology, and immunohistochemistry. The aim of this article is to present a review of the medicolegal literature pertaining to the postmortem biochemical investigations that are associated with heat-related deaths.

Low plasma C-reactive protein level as an early diagnostic tool for heatstroke vs central nervous system-associated infection in the ED.

PURPOSES: Heatstroke (HS) is a life-threatening condition, manifested by systemic inflammation and multiorgan failure. Rapid recognition and treatment are life saving. We report a laboratory-oriented characterization of HS by low plasma C-reactive protein (CRP) level and propose its usefulness in distinguishing this type of hyperpyrexia from central nervous system-associated high core temperature. METHODS: After institutional review board approval, records of patients admitted to general intensive care unit between August 2008 and September 2011 with core temperature 39.0°C or higher due to HS or meningoencephalitis (ME) were reviewed. Patients' demographics, CRP on admission and 24 to 48 hours later, serum creatinine, creatine phosphokinase, platelets count, international normalized ratio, alanine transaminase, serum pH, and lactate levels were retrieved. RESULTS: Thirty-six patients were admitted to the intensive care unit with high core temperature: 19 patients, aged 21 to 85 years, had HS; 17 individuals, aged 22 to 81 years, had ME. None of the HS individuals had infection. Twelve HS patients were previously healthy; in 13 patients, the event occurred postexercise. Mean admission CRP levels was 2.1 ± 3.3 mg/L in the HS group compared with 129 ± 84 mg/L in the ME patients (P < .0001); mean 24- to 48-hour CRP levels were 14.6 ± 16.8 vs 139 ± 98 mg/L, respectively (P < .0001). There were no clinically significant differences between the groups regarding laboratory parameters indicative of end-organ damage. Six HS patients underwent computed tomography and/or lumbar puncture before starting intensive cooling, due to misdiagnosis; 5 of them died subsequently. CONCLUSIONS: Low serum CRP levels characterize non-central nervous system-associated HS. This available laboratory test could identify noninfectious hyperthermic patients upon admission, saving precious time until treatment and avoiding unnecessary diagnostic tests.

Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon.

OBJECTIVE: Excessive activation of coagulation, which can culminate in overt disseminated intravascular coagulation, is a prominent feature of heat stroke. However, neither the mechanism that initiates the coagulation activation nor its pathogenic role is known. We examined whether the tissue factor/factor VIIa complex initiates the coagulation activation in heat stroke and, if so, whether upstream inhibition of coagulation activation through its neutralization may minimize cellular injury and organ dysfunction. We also examined whether coagulation inhibition influences heat stroke-induced fibrinolytic and inflammatory responses. DESIGN: Randomized controlled study. SETTING: Comparative Medicine Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. SUBJECTS: Baboons (Papio Hamadryas). INTERVENTIONS: Twelve anesthetized baboons assigned randomly to recombinant nematode anticoagulant protein c2, a powerful inhibitor of tissue factor/factor VIIa-dependent coagulation (n = 6), or a control group (n = 6) were heat-stressed in a prewarmed neonatal incubator at 44-47°C until systolic blood pressure fell <90 mm Hg, signaling the onset of severe heat stroke. Recombinant nematode anticoagulant protein c2 was administered as a single intravenous dose of 30 µg/kg body weight at onset of heat stroke. The control group received an equivalent volume of sterile saline intravenously. MEASUREMENTS AND MAIN RESULTS: Heat stroke was associated with coagulation activation and fibrin formation as evidenced by the increased plasma thrombin-antithrombin complexes, endogenous thrombin potential, and D-dimer levels. Recombinant nematode anticoagulant protein c2 induced significant inhibition of thrombin generation and fibrin formation. Inhibition of coagulation in recombinant nematode anticoagulant protein c2-treated animals did not influence either fibrinolysis (assessed by tissue plasminogen activator, plasmin-α2-antiplasmin complexes, and plasminogen activator inhibitor) or the release of pro- and anti-inflammatory cytokines. No difference in markers of cell injury and organ dysfunction was observed between recombinant nematode anticoagulant protein c2-treated and control groups. CONCLUSIONS: Tissue factor/factor VIIa-dependent pathway initiates coagulation activation in induced-heat stroke in the baboon without an effect on fibrinolysis and inflammation. The findings suggest also that coagulation activation is not a prerequisite of cell injury and organ dysfunction.

Serum sodium abnormalities during nonexertional heatstroke: incidence and prognostic values.

BACKGROUND: Although heatstroke is often associated with dehydration, the clinical significance of serum sodium abnormalities in patients with heat-related illness during heat wave has been poorly documented. METHOD: We evaluated 1263 patients (age, 82±15 years; body temperature, 40.1°C+1.2°C) admitted to emergency departments during the August 2003 heat wave in Paris, having a core temperature greater than 38.5°C and measurement of serum sodium concentrations. Patients were classified according to our previously described risk score of death. RESULTS: Hyponatremia (<135 mmol/L) was reported in 409 (32%) and hypernatremia (>145 mmol/L) in 220 patients (17%). One-year survival was significantly decreased in patients with hypernatremia (45%; P=.004) but not in those with hyponatremia (58%; P=.86) as compared with patients with serum sodium concentration in the reference range (57%). Using Cox regression, only hypernatremia was an independent prognostic factor (hazard ratio, 1.35; 95% confidence interval, 1.09-1.36) when risk score was taken into account. Using logistic regression, 2 variables were independently associated with hyponatremia (heatstroke severity score and blood urea nitrogen-creatinine ratio<100). Conversely, 5 variables were independently associated with hypernatremia (living in an institution, dementia, serum creatinine>120 µmol/L, a blood urea nitrogen-creatinine ratio >100, and absence of long-term diuretic intake). CONCLUSIONS: Serum sodium abnormalities are frequently observed in patients with a nonexertional heatstroke during heat wave; however, only hypernatremia should be considered as an independent risk factor of death. Rapid measurement of serum sodium concentration is mandatory to appropriately guide electrolyte resuscitation.

Serum procalcitonin predicting mortality in exertional heatstroke.

BACKGROUND: The aim of this study was to test if Procalcitonin PCT value at the time of admission is a predictor of mortality and/or a diagnostic marker of concomitant infection in exertional heatstroke. METHODS: 68 patients with exertional heatstroke admitted to the multidisciplinary intensive care unit were studied. Serum PCT was detected by means of a specific and ultrasensitive immunoluminometric assay within 2 h of admission. The Acute Physiology and Chronic Health Evaluation (APACHE) II score was evaluated within 24 h of admission. RESULTS: There was no significant difference in PCT levels between concomitant infection and non-infection patients (p=0.712). Elevated PCT level in exertional heatstroke patients was associated with a more critical pathological state. PCT values in patients with multiple organ dysfunction syndrome (MODS) were significantly higher than those without MODS (p=0.007.). PCT values were also positively correlated with APACHE II scores (r=0.588, p=0.016). PCT values in non-survivors were higher than in survivors at univariate regression analysis (p=0.017). After adjusting for confounders, PCT concentration also remained an independent determinant of mortality (OR 2.98; 95% CI 1.02 to 4.41; p=0.039). Receiver operating characteristic curve for PCT concentration was located above the reference line, which shows an association with mortality. The area under the curve for PCT concentration (0.705; 95% CI 0.547 to 0.862) was statistical significantly (p=0.019). As a predictor of mortality, PCT value was inferior to APACHE II score. CONCLUSIONS: PCT value at the time of admission is an independent predictor of mortality, but maybe not a good indicator of concomitant infection in exertional heatstroke.

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

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

Early elevated HMGB1 level predicting the outcome in exertional heatstroke.

BACKGROUND: Heatstroke is generally considered as a syndrome of hyperthermia associated with systemic inflammation leading to multiorgan dysfunction. High mobility group box-1 protein (HMGB1) has recently been identified as a late mediator of systemic inflammation inducing multiorgan dysfunction. Elevation of plasma HMGB1 in heatstroke has been observed in animals, but there is no data available about its changes in heatstroke patients. The objectives of this study are to observe the time course of plasma HMGB1 changes and assess its prognostic value in patients with exertional heatstroke. METHODS: Blood samples were taken from the patients with exertional heatstroke. Plasma HMGB1 level was detected by the enzyme-linked immunosorbent assay. C-reactive protein level was measured using a fully automated IMMAGE Immunochemistry System. Secreted HMGB1 in the culture supernatant of peripheral blood monocyte was assessed by immunoblotting. Acute Physiology and Chronic Health Evaluation II score was evaluated within 24 hours of admission. RESULTS: HMGB1 released into circulation at early stage, with peak levels occurring within 6 hours to 13 hours postheatstroke. Plasma HMGB1 levels remained markedly elevated in the following 6 days postheatstroke when compared with healthy volunteers (p<0.005). Positive correlation (r=0.798, p<0.001) was found between Acute Physiology and Chronic Health Evaluation II score and HMGB1 level at admission. HMGB1 levels at admission between survivors and nonsurvivors were significantly different (p<0.001). Receiver operating curve analysis showed that at a level of 47 ng/mL, HMGB1 level at admission indicated lethality with 77.4% sensitivity and 84.2% specificity. CONCLUSIONS: HMGB1 level at admission is an indicator of the severity of illness and a useful mortality predictor in exertional heatstroke.

Exosomes Derived From Heat Stroke Cases Carry miRNAs Associated With Inflammation and Coagulation Cascade.

The pathological mechanism underlying heat stroke (HS) is associated with the dysbalanced inflammation and coagulation cascade. Cell-derived circulating extracellular vesicles (EVs), as a novel pathway mediating intercellular communication, are associated with the immune response and inflammation in critical inflammatory syndromes, such as sepsis. Although these vesicles contain genetic material correlated with their biological function, their molecular cargo during HS remains unknown. In this study, we evaluate the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) associated with inflammatory responses and coagulation cascade in exosomes of patients with HS. Blood samples were collected from three patients with HS at the time of admission to the intensive care unit; three healthy volunteers were selected as control. Exosomes were isolated using ultracentrifugation, and their miRNA content was profiled using next-generation sequencing; mRNA content was evaluated using qPCR array. Compared with those from healthy volunteers, exosomes from patients with HS showed substantial changes in the expression of 202 exosomal miRNAs (154 upregulated and 48 downregulated miRNAs). The most upregulated miRNAs included miR-511-3p, miR-122-5p, miR-155-3p, miR-1290, and let7-5p, whereas the most downregulated ones included miR-150-3p, 146a-5p, and 151a-3p. Gene ontology enrichment of the miRNAs of patients with HS compared with control subjects were associated mostly with inflammatory response, including T cell activation, B cell receptor signaling, dendritic cell chemotaxis and leukocyte migration, and platelet activation and blood coagulation. The identified miRNAs were primarily enriched to the signal transduction pathways namely, T cell receptor signaling, Ras signaling, chemokine signaling, platelet activation, and leukocyte transendothelial migration, all of which are associated with inflammation and hemostasis. Multiple targeted mRNAs associated with the inflammatory response, blood coagulation, and platelet activation were further verified in serum exosomes. Exosomes from patients with HS convey miRNAs and mRNAs associated with pathogenic pathways, including inflammatory response and coagulation cascade. Exosomes may represent a novel mechanism for intercellular communication during HS.