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 fi tting 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 fi tting 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.

Glutamine supplementation attenuates intestinal apoptosis by inducing heat shock protein 70 in heatstroke rats

BACKGROUND:Heatstroke is the most hazardous heat-related illness and has a high fatality rate.We investigated whether glutamine supplementation could have a protective effect on heatstroke rats.METHODS:Twenty-five 12-week-old male Wistar rats(weight 305±16 g)were randomly divided into a control group(n=5),heatstroke(HS)group(n=10),and heatstroke+glutamine(HSG)group(n=10).Seven days before heat exposure,glutamine(0.4 g/[kg·d])was administered to the rats in the HSG group by gavage every day.Three hours after heat exposure,serum samples were collected to detect white blood cells,coagulation indicators,blood biochemical indicators,and inflammatory cytokines in the rats.The small intestine tissue was stained to analyze pathological structural changes and apoptosis.Finally,immunohistochemistry and Western blotting were used to analyze the expression levels of heat shock protein 70(HSP70).Multiple comparisons were analyzed by using one-way analysis of variance,and the Bonferroni test was conducted for the post hoc comparisons.RESULTS:After heat exposure,the core temperature of the HS group(40.65±0.31°C)was higher than the criterion of heatstroke,whereas the core temperature of the HSG group(39.45±0.14°C)was lower than the criterion.Glutamine supplementation restored the increased white blood cells,coagulation indicators,blood biochemical indicators,and inflammatory cytokines that were induced by heatstroke to normal levels.The intestinal mucosa was injured,and the structure of tight junctions was damaged in the HS group;however,the structure of intestinal mucosal epithelial cells was stable in the HSG group.Glutamine supplementation alleviated intestinal apoptosis and up-regulated HSP70 expression.CONCLUSION:Glutamine supplementation may alleviate intestinal apoptosis by inducing the expression of HSP70 and have a protective effect on heatstroke rats.

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 nonsurvivors(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.

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

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

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℃,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.

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

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

Combination Treatment with Gua Sha and Blood-letting Causes Attenuation of Systemic Inflammation,Activated Coagulation,Tissue Ischemia and Injury during Heatstroke in Rats

Objective： Gua Sha and Blood-letting at the acupoints were Chinese traditional therapies for heatstroke. The purpose of present study was to assess the therapeutic effect of Gua Sha on the DU Meridian and Bladder Meridian combined with Blood-letting acupoints at Shixuan （EX-UE 11） and Weizhong （BL 40） on heatstroke. Methods： Anesthetized rats, immediately after the onset of heatstroke, were divided into four major groups： Gua Sha group, Blood-letting group, Gua Sha combined with Blood-letting group and model group. They were exposed to ambient temperature of 43℃ to induce heatstroke. Another group of rats were exposed to room temperature （26℃） and used as normal control group. Their survival times were measured. In addition, their physiological and biochemical parameters were continuously monitored. Results： When rats underwent heatstroke, their survival time values were found to be 21-25 min. Treatment of Gua Sha combined with Blood- letting greatly improved the survival time （230 ± 22 rain） during heatstroke. All heatstoke animals displayed and activated coagulation evidenced by increased prothrombin time （PT）, activated partial thromboplastin time （aPTT）, D-dimer, and decreased platelet count, protein C. Furthermore, the animals displayed systemic inflammation evidenced by increased the serum levels of cytokines interleukin-1β （IL-1β）, tumor necrosis factor α （TNF-α） and malondialdehyde （MDA）. Biochemical markers evidenced by cellular ischemia and injury/dysfunction included increased plasma levels of blood urea nitrogen （BUN）, creatinine, serum glutamic oxaloacetic transaminase （SGOT）, serum glutamic pyruvic transaminase （SGPT）, and alkaline phosphatase （ALP） were all elevated during heatstroke. Core temperatures （Tco） were also increased during heatstroke. In contrast, the values of mean arterial pressure were significantly lower during heatstroke. These heatstroke reactions were all significantly suppressed by treatment of Gua Sha and Blood-letting, especially the combination therapy. Conclusion： Gua Sha combined with Blood-letting after heatstroke may improve survival by ameliorating systemic inflammation, hypercoagulable state, and tissue ischemia and injury in multiple organs.

Characteristics and Outcome of Exertional Heatstroke Patients Complicated by Acute Hepatic Injury:A Cohort Study

Background and Aims:Exertional heatstroke(EHS)is associated with strenuous physical activity in hot environments.The present study aimed to investigate dynamic changes of hepatic function indices in EHS patients and determine risk factors for death.Methods:This single-center retrospective cohort study considered all patients with EHS admitted to the intensive care unit at the General Hospital of Southern Theater Command of PLA from October 2008 to May 2019.Data on general characteristics,organ function parameters,and the 90-day outcome of enrolled patients were collected.Hepatic indices were collected dynamically,and patients with acute hepatic injury(AHI)were identified by plasma total bilirubin(TBIL)≥34.2μmol/L and an international normalized ratio≥1.5,or with any grade of hepatic encephalopathy.Results:In patients who survived,TBIL,alanine aminotransferase and aspartate aminotransferase were increased at 24 h,peaked at 2–3 days,and began to decrease at 5 days.In non-survivors,TBIL continuously increased post-admission.The area under the receiver operating characteristic curve for the prediction of mortality based on sequential organ failure assessment(SOFA)scores was 89.8%,and the optimal cutoff value was 7.5.Myocardial injury and infection were identified as independent risk factors for death in EHS patients with AHI.Conclusions:In EHS patients,hepatic dysfunction usually occurred within 24 h.Patients with AHI had more severe clinical conditions,and significantly increased 90-day mortality rates.SOFA scores over 7.5,complicated with myocardial injury or infection,were found to be risk factors for death in EHS patients with AHI.

Relationship between Coagulation Function and HMGB1 in Rats with Severe Heatstroke

Objective: To investigate the effect of severe heatstroke on coagulation function in rats and the possible mechanism of high-mobility group protein B1(HMGB1)involved in the regulation of coagulation function. Methods: A total of 24 male SD rats were randomly divided into control group, mild group, moderate group and severe group,with 6 rats in each group. The rats in mild group, moderate group and severe group were continuously exposed to 40℃ and 10% humidity environment, then taken out and rewarmed to complete the heat stroke rat modeling process after the experiments were conducted for 70, 110, and 145 min, respectively. The levels of HMGB1 in peripheral blood were detected by enzyme-linked immunosorbent assay(ELISA) before modeling and at 0 and 3 h after modeling, and coagulation tests were used to determine prothrombin time(PT), activated partial thromboplastin time(APTT), and prothrombin time(APT) at the same time points in the rats. The correlation between HMGB1 and coagulation parameters was determined by Pearson correlation. Results: In the severe group, HMGB1 was(2372.45±97.85) pg/ml and(2547.72±117.67) pg/ml at 0 and 3 h after modeling, respectively, and the levels of PT, APTT and Fib were higher than those before modeling and at 3 h after modeling. There was significant correlation between HMGBI and APTT, Fib(r=0.978, 0.785, P=0.000, 0.000). There were positive correlations between HMGBI and PT, APTT, Fib(r=0.634,0.976,0.889, P=0.001,0.000,0.000).Conclusion: HMGB1 may be involved in the pathogenesis of coagulation dysfunction in rats with severe heatstroke by regulating the activation of coagulation cells, and the level of HMGB1 in rats with severe heatstroke increases and still tends to increase after rewarming.

Exertional heat stroke with pronounced presentation of microangiopathic hemolytic anemia:A case report

BACKGROUND Exertional heat stroke(EHS)is a critical condition arising from prolonged physical exertion in high temperatures that typically presents with normal hemoglobin levels.However,atypical presentations can also occur,leading to significant complications such as hemolytic anemia and organ dysfunction.CASE SUMMARY This case report describes a male patient who experienced moderate-to-severe anemia that was difficult to correct,with a confirmed diagnosis of microangiopathic hemolytic anemia accompanying multiple organ dysfunction syndrome,indicative of critical EHS.Despite intensive resuscitation efforts,the patient’s condition deteriorated,necessitating admission to the intensive care unit for advanced management.CONCLUSION This case highlights the importance of recognizing atypical presentations of EHS,particularly that with significant hemolytic anemia and concurrent organ failure.Clinicians should maintain a high level of suspicion for these complications in patients displaying symptoms of heat-related illness,especially when caused by strenuous activity,as early diagnosis and intervention are crucial to improve patient outcomes.

Pathological changes in the lung and brain of mice during heat stress and cooling treatment

BACKGROUND： Heatstroke often leads to multiple organ dysfunction syndrome （MODS） with a death rate of 40% or a neurological morbidity of 30%. These high rates in patients with heatstroke are largely due to the progression of heat stress to MODS, resulting in no specifi c treatment available. This study aimed to develop a mouse model of heat stress and determine the pathological changes in the lung and brain during heat stress and cooling treatment.METHODS： A mouse model of heat stress was established in a pre-warmed incubator set at 35.5 ± 0.5°C and with a relative humidity of 60% ± 5%. Rectal temperature was monitored, and at a temperature of 39 °C, 40 °C, 41 °C, or 42 °C, the mice were sacrifi ced. The remaining animals were removed from the incubator and cooled at an ambient temperature of 25 ± 0.5 °C and a humidity of 35% ± 5% for 12 or 24 hours at a temperature of 41 °C or for 6 hours at a temperature of 42 °C. The control mice were sham-heated at a temperature of 25 ± 0.5 °C and a humidity of 35% ± 5%. The lungs and brains of all animals were isolated. Hematoxylin and eosin staining and light microscopy were performed to detect pathological changes.RESULTS： All mice demonstrated a uniform response to heat stress. A low degree of heat stress induced marked pathological changes of the lungs. With the rise of the temperature to 42°C, progressively greater damage to the lungs with further congestion of the lung matrix, asystematic hemorrhage of alveolar space, abscission of alveolar epithelial cells, and disappearance of pulmonary alveolus tissue structure were detected. However, absorption of congestion and hemorrhage as well as recovery of pulmonary alveolus tissue structure was observed following cooling treatment at an ambient temperature. With a low degree of heat stress, the brain only showed moderate edema. Neuronal denaturation and necrosis were detected at a temperature of 42°C. Interestingly, the lesions in the brain were further aggravated at 42 °C regardless of cooling treatment, but recovery was observed after cooling treatment at 41 °C.CONCLUSIONS： The pathological changes of the lungs and brain of mice showed distinctive lesions following heat stress and cooling treatment, and they were correlated with the time and duration of cooling treatment. The results of this study are helpful for further study of the mechanisms linking heatstroke.