Crush syndrome: a review for prehospital providers and emergency clinicians.

INTRODUCTION: Disasters and accidents have occurred with increasing frequency in recent years. Primary disasters have the potential to result in mass casualty events involving crush syndrome (CS) and other serious injuries. Prehospital providers and emergency clinicians stand on the front lines of these patients' evaluation and treatment. However, the bulk of our current knowledge, derived from historical data, has remained unchanged for over ten years. In addition, no evidence-based treatment has been established to date. OBJECTIVE: This narrative review aims to provide a focused overview of, and update on, CS for both prehospital providers and emergency clinicians. DISCUSSION: CS is a severe systemic manifestation of trauma and ischemia involving soft tissue, principally skeletal muscle, due to prolonged crushing of tissues. Among earthquake survivors, the reported incidence of CS is 2-15%, and mortality is reported to be up to 48%. Patients with CS can develop cardiac failure, kidney dysfunction, shock, systemic inflammation, and sepsis. In addition, late presentations include life-threatening systemic effects such as hypovolemic shock, hyperkalemia, metabolic acidosis, and disseminated intravascular coagulation. Immediately beginning treatment is the single most important factor in reducing the mortality of disaster-situation CS. In order to reduce complications from CS, early, aggressive resuscitation is recommended in prehospital settings, ideally even before extrication. However, in large-scale natural disasters, it is difficult to diagnose CS, and to reach and start treatments such as continuous administration of massive amounts of fluid, diuresis, and hemodialysis, on time. This may lead to delayed diagnosis of, and high on-site mortality from, CS. To overcome these challenges, new diagnostic and therapeutic modalities in the CS animal model have recently been advanced. CONCLUSIONS: Patient outcomes can be optimized by ensuring that prehospital providers and emergency clinicians maintain a comprehensive understanding of CS. The field is poised to undergo significant advances in coming years, given recent developments in what is considered possible both technologically and surgically; this only serves to further emphasize the importance of the field, and the need for ongoing research.

Outcome of extracorporeal membrane oxygenation use in severe accidental hypothermia with cardiac arrest and circulatory instability: A multicentre, prospective, observational study in Japan (ICE-CRASH study).

AIM: To elucidate the effectiveness of extracorporeal membrane oxygenation (ECMO) in accidental hypothermia (AH) patients with and without cardiac arrest (CA), including details of complications. METHODS: This study was a multicentre, prospective, observational study of AH in Japan. All adult (aged ≥18 years) AH patients with body temperature ≤32 °C who presented to the emergency department between December 2019 and March 2022 were included. Among the patients, those with CA or circulatory instability, defined as severe AH, were selected and divided into the ECMO and non-ECMO groups. We compared 28-day survival and favourable neurological outcomes at discharge between the ECMO and non-ECMO groups by adjusting for the patients' background characteristics using multivariable logistic regression analysis. RESULTS: Among the 499 patients in this study, 242 patients with severe AH were included in the analysis: 41 in the ECMO group and 201 in the non-ECMO group. Multivariable analysis showed that the ECMO group was significantly associated with better 28-day survival and favourable neurological outcomes at discharge in patients with CA compared to the non-ECMO group (odds ratio [OR] 0.17, 95% confidence interval [CI]: 0.05-0.58, and OR 0.22, 95%CI: 0.06-0.81). However, in patients without CA, ECMO not only did not improve 28-day survival and neurological outcomes, but also decreased the number of event-free days (ICU-, ventilator-, and catecholamine administration-free days) and increased the frequency of bleeding complications. CONCLUSIONS: ECMO improved survival and neurological outcomes in AH patients with CA, but not in AH patients without CA.

Impact of Pelvic Fracture Sites on Fibrinogen Depletion in Patients with Blunt Trauma: A Single-Center Cohort Study.

BACKGROUND: We aimed to examine the association of pelvic fracture sites with the minimum fibrinogen level within 24 h after hospital arrival. METHODS: We conducted a single-center cohort study using health records review. We included patients with pelvic fractures transported by ambulance to a tertiary-care hospital from January 2012 to December 2018 and excluded those transported from other hospitals or aged younger than 16 years. The pelvic fracture was diagnosed and confirmed by trauma surgeons and/or radiologists. We classified the fracture sites of the pelvis as ilium, pubis, ischium, acetabulum, sacrum, sacroiliac joint diastasis, and pubic symphysis diastasis, and each side was counted separately except for pubic symphysis diastasis. We performed linear regression analysis to evaluate the association between pelvic fracture sites and the minimum fibrinogen level within 24 h of arrival. RESULTS: We analyzed 120 pelvic fracture patients. Their mean age was 47.3 years, and 69 (57.5%) patients were men. The median Injury Severity Score was 24, and in-hospital mortality was 10.8%. The mean minimum fibrinogen level within 24 h of arrival was 171.4 mg/dL. Among pelvic fracture sites, only sacrum fracture was statistically significantly associated with the minimum fibrinogen level within 24 h of arrival (estimate, -34.5; 95% CI, -58.6 to -10.4; p = 0.005). CONCLUSIONS: Fracture of the sacrum in patients with pelvic fracture was associated with lower minimum fibrinogen levels within 24 h of hospital arrival and the requirement of blood transfusion.

Effectiveness of high-flow nasal cannula for tracheal intubation in the emergency department.

BACKGROUND: Tracheal intubation in the emergency department (ED) can cause serious complications. Available evidence on the use of a high-flow nasal cannula (HFNC) during intubation in the ED is limited. This study evaluated the effect of oxygen therapy by HFNC on oxygen desaturation during tracheal intubation in the ED. METHODS: This was a single-center before-and-after study designed to compare two groups that received oxygen therapy during intubation: one received conventional oxygen, and the other received oxygen therapy using HFNC. We included non-trauma patients who required tracheal intubation in the ED. Linear regression analysis was performed to evaluate the relationship between oxygen therapy using HFNC and the lowest peripheral oxygen saturation (SpO2) during intubation in the conventional and HFNC groups. RESULTS: The study population included 87 patients (conventional group, n = 67; HFNC group, n = 20). The median lowest SpO2 in the HFNC group was significantly higher than that in the conventional group (94% [84-99%] vs. 85% [76-91%], p = 0.006). The percentage of cases with oxygen desaturation to < 90% during the intubation procedure in the HFNC group was significantly lower than that in the conventional group (40% vs. 63.8%, p = 0.037). The use of HFNC was significantly associated with the lowest SpO2, and the use of HFNC increased the lowest SpO2 during intubation procedures by 3.658% (p = 0.048). CONCLUSION: We found that the use of HFNC during tracheal intubation was potentially associated with a higher lowest SpO2 during the procedure in comparison to conventional oxygen administration in non-trauma patients in the ED.

Influence of the coronavirus disease 2019 (COVID-19) pandemic on the incidence of heat stroke and heat exhaustion in Japan: a nationwide observational study based on the Heatstroke STUDY 2019 (without COVID-19) and 2020 (with COVID-19).

AIM: To assess heat stroke and heat exhaustion occurrence and response during the coronavirus disease 2019 pandemic in Japan. METHODS: This retrospective, multicenter, registry-based study describes and compares the characteristics of patients between the months of July and September in 2019 and 2020. Factors affecting heat stroke and heat exhaustion were statistically analyzed. Cramér's V was calculated to determine the effect size for group comparisons. We also investigated the prevalence of mask wearing and details of different cooling methods. RESULTS: No significant differences were observed between 2019 and 2020. In both years, in-hospital mortality rates just exceeded 8%. Individuals >65 years old comprised 50% of cases and non-exertional onset (office work and everyday life) comprised 60%-70%, respectively. The recommendations from the Working Group on Heat Stroke Medicine given during the coronavirus disease pandemic in 2019 had a significant impact on the choice of cooling methods. The percentage of cases, for which intravascular temperature management was performed and cooling blankets were used increased, whereas the percentage of cases in which evaporative plus convective cooling was performed decreased. A total of 49 cases of heat stroke in mask wearing were reported. CONCLUSION: Epidemiological assessments of heat stroke and heat exhaustion did not reveal significant changes between 2019 and 2020. The findings suggest that awareness campaigns regarding heat stroke prevention among the elderly in daily life should be continued in the coronavirus disease 2019 pandemic. In the future, it is also necessary to validate the recommendations of the Working Group on Heatstroke Medicine.

The accuracy of contrast-enhanced computed tomography scans to detect postpartum haemorrhage: an observational study.

INTRODUCTION: Postpartum haemorrhage is a major cause of maternal mortality. Although contrast-enhanced computed tomography (CE-CT) is useful to reveal arterial bleeding, its accuracy in postpartum haemorrhage is unclear. The aim of this study was to evaluate the accuracy of CE-CT scanning in detecting postpartum haemorrhage. METHODS: This was a retrospective observational study. We included patients with postpartum haemorrhage treated by emergency physicians in collaboration with obstetricians. We calculated the sensitivity, specificity, and positive and negative predictive values for CE-CT scanning to detect arterial bleeding. RESULTS: CE-CT scanning was performed in 52 patients, and 31 patients had extravasation. The sensitivity of CE-CT scanning to detect arterial extravasation was 100% (15/15), specificity was 28.6% (2/7), positive predictive value was 75% (15/20), and negative predictive value was 100% (2/2). CONCLUSION: We showed the sensitivity of CE-CT scanning to detect arterial extravasation in patients with postpartum haemorrhage to be 100%.

Evaluation of urinary extravasation after non-operative management of traumatic renal injury: a multi-center retrospective study.

PURPOSE: Urinary extravasation is one of the major complications after non-operative management of traumatic renal injury and may lead to urinary tract infection and sepsis. The purpose of this study was to evaluate these factors in patients with traumatic renal injury. METHODS: This was a multi-center, retrospective, observational study performed at three tertiary referral hospitals in Osaka prefecture. We included patients with traumatic renal injury transported to the centers between January 2008 and December 2018. We excluded patients who either died or underwent nephrectomy within 24 h after admission. We investigated the occurrence of urinary extravasation and the related factors after traumatic renal injury using multivariable logistic regression analysis. RESULTS: In total, 146 patients were eligible for analysis. Their median age was 44 years and 68.5% were male. Their median Injury Severity Score was 17. Renal injuries were graded as American Association for Surgery of Trauma (AAST) grade I in 33 (22.6%), II in 27 (18.5%), III in 38 (26.0%), IV in 28 (19.2%), and V in 20 (13.7%) patients. Urinary extravasation was diagnosed in 26 patients (17.8%) and was statistically significantly associated with AAST grades IV-V (adjusted odds ratio, 33.8 [95% confidence interval 7.12-160], p < 0.001). CONCLUSION: We observed urinary extravasation in 17.8% of patients with non-operative management of traumatic renal injury and the diagnosed was made in mostly within 7 days after admission. In this study, the patients with AAST grade IV-V injury were associated with having urinary extravasation.

Accidental hypothermia: characteristics, outcomes, and prognostic factors-A nationwide observational study in Japan (Hypothermia study 2018 and 2019).

AIM: This study describes the clinical characteristics and outcomes as well as the prognostic factors of patients with accidental hypothermia (AH) using Japan's nationwide registry data. METHODS: The Hypothermia study 2018 and 2019, which included patients aged 18 years or older with a body temperature of 35°C or less, was a multicenter registry conducted at 87 and 89 institutions throughout Japan, with data collected from December 2018 to February 2019 and December 2019 to February 2020, respectively. RESULTS: In total, 1363 patients were enrolled in the registry, of which 1194 were analyzed in this study. The median (interquartile range) age was 79 (68-87) years, and the median (interquartile range) body temperature at the emergency department was 30.8°C (28.4-33.6°C). Forty-three percent of patients with AH had a mild condition, 35.2% moderate, and 21.9% severe. AH occurred in an indoor setting in 73.4% and was caused by acute medical illness in 49.3% of patients. A total of 101 (8.5%) patients suffered from cardiopulmonary arrest on arrival at the hospital. The overall 30-day mortality rate was 24.5%, the median (interquartile range) intensive care unit stay was 4 (2-7) days, and the median (interquartile range) hospital stay was 13 (4-27) days. In the multivariable logistic analysis, the prognostic factors were age (≥75 years old), male, activities of daily living (needing total assistance), cause of AH (trauma, alcohol), Glasgow Coma Scale score, and potassium level (>5.5 mEq/L). CONCLUSION: The mortality rate of AH was 24.5% in Japan. The prognostic factors developed in this study may be useful for the early prediction, prevention, and awareness of severe AH.

Association between frailty and mortality among patients with accidental hypothermia: a nationwide observational study in Japan.

BACKGROUND: Frailty has been associated with a risk of adverse outcomes, and mortality in patients with various conditions. However, there have been few studies on whether or not frailty is associated with mortality in patients with accidental hypothermia (AH). In this study, we aim to determine this association in patients with AH using Japan's nationwide registry data. METHODS: The data from the Hypothermia STUDY 2018&19, which included patients of ≥18 years of age with a body temperature of ≤35 °C, were obtained from a multicenter registry for AH conducted at 120 institutions throughout Japan, collected from December 2018 to February 2019 and December 2019 to February 2020. The clinical frailty scale (CFS) score was used to determine the presence and degree of frailty. The primary outcome was the comparison of mortality between the frail and non-frail patient groups. RESULTS: In total, 1363 patients were included in the study, of which 920 were eligible for the analysis. The 920 patients were divided into the frail patient group (N = 221) and non-frail patient group (N = 699). After 30-days of hospitalization, 32.6% of frail patients and 20.6% of non-frail patients had died (p < 0.001). Frail patients had a significantly higher risk of 90-day mortality (Hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.25-2.17; p < 0.001). Based on the Cox proportional hazards analysis using multiple imputation, after adjustment for age, potassium level, lactate level, pH value, sex, CPK level, heart rate, platelet count, location of hypothermia incidence, and rate of tracheal intubation, the HR was 1.69 (95% CI, 1.25-2.29; p < 0.001). CONCLUSIONS: This study showed that frailty was associated with mortality in patients with AH. Preventive interventions for frailty may help to avoid death caused by AH.

Machine learning-based mortality prediction model for heat-related illness.

In this study, we aimed to develop and validate a machine learning-based mortality prediction model for hospitalized heat-related illness patients. After 2393 hospitalized patients were extracted from a multicentered heat-related illness registry in Japan, subjects were divided into the training set for development (n = 1516, data from 2014, 2017-2019) and the test set (n = 877, data from 2020) for validation. Twenty-four variables including characteristics of patients, vital signs, and laboratory test data at hospital arrival were trained as predictor features for machine learning. The outcome was death during hospital stay. In validation, the developed machine learning models (logistic regression, support vector machine, random forest, XGBoost) demonstrated favorable performance for outcome prediction with significantly increased values of the area under the precision-recall curve (AUPR) of 0.415 [95% confidence interval (CI) 0.336-0.494], 0.395 [CI 0.318-0.472], 0.426 [CI 0.346-0.506], and 0.528 [CI 0.442-0.614], respectively, compared to that of the conventional acute physiology and chronic health evaluation (APACHE)-II score of 0.287 [CI 0.222-0.351] as a reference standard. The area under the receiver operating characteristic curve (AUROC) values were also high over 0.92 in all models, although there were no statistical differences compared to APACHE-II. This is the first demonstration of the potential of machine learning-based mortality prediction models for heat-related illnesses.

Clinical characteristics, prognostic factors, and outcomes of heat-related illness (Heatstroke Study 2017-2018).

AIM: Heat-related illness is common, but its epidemiology and pathological mechanism remain unclear. The aim of this study was to report current clinical characteristics, prognostic factors, and outcomes of heat-related illness in Japan. METHODS: We undertook a prospective multicenter observational study in Japan. Only hospitalized patients with heat-related illness were enrolled from 1 July to 30 September 2017 and 1 July to 30 September 2018. RESULTS: A total of 763 patients were enrolled in the study. Median age was 68 years (interquartile range, 49-82 years) and median body temperature on admission was 38.2°C (interquartile range, 36.8-39.8°C). Non-exertional cause was 56.9% and exertional cause was 40.0%. The hospital mortality was 4.6%. The median Japanese Association for Acute Medicine disseminated intravascular coagulation (JAAM DIC), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores on admission were 1 (0-2), 4 (2-6), and 13 (8-22), respectively. To predict hospital mortality, areas under the receiver operating characteristic curves were 0.776 (JAAM DIC score), 0.825 (SOFA), and 0.878 (APACHE II). There were 632 cases defined as heatstroke by JAAM heat-related illness criteria, 73 cases diagnosed as having DIC. A total of 16.6% patients had poor neurological outcome (modified Rankin Scale ≥ 4) at hospital discharge. In the multivariate analysis, Glasgow Coma Scale and platelets were independent predictors of mortality. Type of heatstroke, Glasgow Coma Scale, and platelets were independent predictors of poor neurological outcome. Body temperature was not associated with mortality or poor neurological outcome. CONCLUSIONS: In this study, hospital mortality of heat-related illness was <5%, one-sixth of the patients had poor neurological outcome. The APACHE II, SOFA, and JAAM DIC scores predicted hospital mortality. Body temperature was not associated with mortality or poor neurological outcome.

Comparison between the Bouchama and Japanese Association for Acute Medicine Heatstroke Criteria with Regard to the Diagnosis and Prediction of Mortality of Heatstroke Patients: A Multicenter Observational Study.

BACKGROUND: This study aims to compare the Bouchama heatstroke (B-HS) and Japanese Association for Acute Medicine heatstroke (JAAM-HS) criteria with regard to the diagnosis and prediction of mortality and neurological status of heatstroke patients. METHODS: This multicenter observational study recruited eligible patients from the emergency departments of 110 major hospitals in Japan from 1 July to 30 September, 2014. RESULTS: A total of 317 patients (median age, 65 years; interquartile range, 39-80 years) were included and divided into the B-HS, JAAM-HS, and non-HS groups, with each group consisting of 97, 302, and 15 patients, respectively. The JAAM-HS (1.0; 95% confidence interval [CI], 0.87-1.0) and B-HS (0.29; 95% CI, 0.14-0.49) criteria showed high and low sensitivity to mortality, respectively. Similarly, the JAAM-HS (1.0; 95% CI, 0.93-1.0) and B-HS (0.35; 95% CI, 0.23-0.49) criteria showed high and low sensitivity to poor neurological status, respectively. Meanwhile, the sequential organ failure assessment (SOFA) scores demonstrated good accuracy in predicting mortality among heat-related illness (HRI) patients. However, both JAAM-HS and B-HS criteria could not predict in-hospital mortality. The AUC of the SOFA score for mortality was 0.83 (day 3) among the HRI patients. The patients' neurological status was difficult to predict using the JAAM-HS and B-HS criteria. Concurrently, the total bilirubin level could relatively predict the central nervous system function at discharge. CONCLUSIONS: The JAAM-HS criteria showed high sensitivity to mortality and could include all HRI patients who died. The JAAM-HS criterion was considered a useful tool for judgement of admission at ED. Further investigations are necessary to determine the accuracy of both B-HS and JAAM-HS criteria in predicting mortality and neurological status at discharge.

Evaluation of a Novel Classification of Heat-Related Illnesses: A Multicentre Observational Study (Heat Stroke STUDY 2012).

The Japanese Association for Acute Medicine Committee recently proposed a novel classification system for the severity of heat-related illnesses. The illnesses are simply classified into three stages based on symptoms and management or treatment. Stages I, II, and III broadly correspond to heat cramp and syncope, heat exhaustion, and heat stroke, respectively. Our objective was to examine whether this novel severity classification is useful in the diagnosis by healthcare professionals of patients with severe heat-related illness and organ failure. A nationwide surveillance study of heat-related illnesses was conducted between 1 June and 30 September 2012, at emergency departments in Japan. Among the 2130 patients who attended 102 emergency departments, the severity of their heat-related illness was recorded for 1799 patients, who were included in this study. In the patients with heat cramp and syncope or heat exhaustion (but not heat stroke), the blood test data (alanine aminotransferase, creatinine, blood urea nitrogen, and platelet counts) for those classified as Stage III were significantly higher than those of patients classified as Stage I or II. There were no deaths among the patients classified as Stage I. This novel classification may avoid underestimating the severity of heat-related illness.

A novel early risk assessment tool for detecting clinical outcomes in patients with heat-related illness (J-ERATO score): Development and validation in independent cohorts in Japan.

BACKGROUND: We sought to develop a novel risk assessment tool to predict the clinical outcomes after heat-related illness. METHODS: Prospective, multicenter observational study. Patients who transferred to emergency hospitals in Japan with heat-related illness were registered. The sample was divided into two parts: 60% to construct the score and 40% to validate it. A binary logistic regression model was used to predict hospital admission as a primary outcome. The resulting model was transformed into a scoring system. RESULTS: A total of 3,001 eligible patients were analyzed. There was no difference in variables between development and validation cohorts. Based on the result of a logistic regression model in the development phase (n = 1,805), the J-ERATO score was defined as the sum of the six binary components in the prehospital setting (respiratory rate≥22 /min, Glasgow coma scale<15, systolic blood pressure≤100 mmHg, heart rate≥100 bpm, body temperature≥38°C, and age≥65 y), for a total score ranging from 0 to 6. In the validation phase (n = 1,196), the score had excellent discrimination (C-statistic 0.84; 95% CI 0.79-0.89, p<0.0001) and calibration (P>0.2 by Hosmer-Lemeshow test). The observed proportion of hospital admission increased with increasing J-ERATO score (score = 0, 5.0%; score = 1, 15.0%; score = 2, 24.6%; score = 3, 38.6%; score = 4, 68.0%; score = 5, 85.2%; score = 6, 96.4%). Multivariate analyses showed that the J-ERATO score was an independent positive predictor of hospital admission (adjusted OR, 2.43; 95% CI, 2.06-2.87; P<0.001), intensive care unit (ICU) admission (3.73; 2.95-4.72; P<0.001) and in-hospital mortality (1.65; 1.18-2.32; P = 0.004). CONCLUSIONS: The J-ERATO score is simply assessed and can facilitate the identification of patients with higher risk of heat-related hospitalization. This scoring system is also significantly associated with the higher likelihood of ICU admission and in-hospital mortality after heat-related hospitalization.

Prognostic significance of disseminated intravascular coagulation in patients with heat stroke in a nationwide registry.

PURPOSE: Heat stroke (HS) induces disseminated intravascular coagulation (DIC); however, the prognostic significance of DIC in patients with HS has not yet been fully assessed in large populations. The aim of this study was to examine the prognostic significance of DIC in patients with HS using a nationwide registry. MATERIALS AND METHODS: Data regarding HS were obtained and analyzed from three prospective, observational, multicenter HS registries (HSRs): 2010, 2012, and 2014. Univariate and multivariate analyses were performed to identify independent predictors of hospital death. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) diagnostic criteria, with a total score≥4 implying a DIC diagnosis. RESULTS: In total, 705 (median age, 68years; 501 men) were included in this study. Hospital mortality was 7.1% (50 patients). Multiple regression analysis revealed that hospital mortality was significantly associated with presence of DIC (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.09-4.27; p=0.028). Mortality worsened as the DIC score increased, and increased remarkably to approximately 10% when the DIC score was 2. CONCLUSIONS: Presence of DIC was an independent prognostic factor of hospital mortality in patients with HS. Hematological dysfunction represents potential target for specific therapies in HS.

Therapeutic Effectiveness of Anti-RAGE Antibody Administration in a Rat Model of Crush Injury.

Crush injury patients often have systemic inflammatory response syndrome that leads to multiple organ failure. Receptor for advanced glycation endproducts (RAGE) functions as a pattern recognition receptor that regulates inflammation. We evaluated the effects of anti-RAGE antibody in a crush injury model. Pressure was applied to both hindlimbs of rats for 6 h by 3.0-kg blocks and then released. Animals were randomly divided into the sham (RAGE-Sh) group, crush (RAGE-Ctrl) group or anti-RAGE antibody-treated crush (RAGE-Tx) group. Samples were collected at 3, 6 and 24 h after releasing pressure. In the RAGE-Ctrl group, fluorescent immunostaining in the lung showed upregulated RAGE expression at 3 h. The serum soluble RAGE (sRAGE) level, which reflects the amount of RAGE expression in systemic tissue, increased at 6 h. Serum interleukin 6 (IL-6; systemic inflammation marker) increased immediately at 3 h. Histological analysis revealed lung injury at 6 and 24 h. Administration of anti-RAGE antibody before releasing compression inhibited upregulated RAGE expression in the lung alveoli, suppressed RAGE-associated mediators sRAGE and IL6, attenuated the lung damage and improved the 7-day survival rate. Collectively, our results indicated that the use of anti-RAGE antibody before releasing compression is associated with a favourable prognosis following crush injury.

The Beneficial Effects of ETS-GS, a Novel Vitamin E Derivative, on a Rat Model of Crush Injury.

Crush syndrome is a devastating condition leading to multiple organ failure. The mechanisms by which local traumatic injuries affect distant organs remain unknown. ETS-GS is a novel water-soluble, stable anti-oxidative agent composed of vitamin E derivative. Given that one of the main pathophysiological effects in crush syndrome is massive ischemia-reperfusion, reactive oxygen species (ROS) generated from the injured extremities would be systemically involved in distant organ damage. We investigated whether ETS-GS could suppress inflammatory response and improve mortality in a rat model of crush injury. Crush injury was induced by compression of bilateral hindlimbs for 6 h followed by release of compression. Seven-day survival was significantly improved by ETS-GS treatment. To estimate anti-oxidative and anti-inflammatory effects of ETS-GS, serum was collected 6 and 20 h after the injury. ETS-GS treatment significantly dampened the up-regulation of malondialdehyde and reduction of superoxide dismutase in the serum, which were induced by crush injury. Serum levels of interleukin 6 and high mobility group box 1 were significantly decreased in the ETS-GS group compared with those in the control group. Lung damage shown by hematoxylin-eosin staining at 20 h after the injury was ameliorated by the treatment. Ex vivo imaging confirmed that ETS-GS treatment reduced ROS generation in both the lung and the muscle following crush injury. The administration of ETS-GS could suppress ROS generation, systemic inflammation, and the subsequent organ damage, thus improving survival in a rat model of crush injury. These findings suggest that ETS-GS can become a novel therapeutic agent against crush injury.

The risk of pediatric bicycle handlebar injury compared with non-handlebar injury: a retrospective multicenter study in Osaka, Japan.

BACKGROUND: Bicycle accidents are one of the major causes of unintentional traumatic injury in childhood. The purpose of this study was to examine characteristics and risks of handlebar injury in childhood. METHODS: We conducted a more than 5-year retrospective survey of patients under 15 years of age with bicycle-related injuries admitted to eight urban tertiary emergency centers in Osaka, Japan. Patients were divided into the direct-impact handlebar injury (HI) group and the non-handlebar injury (NHI) group. RESULTS: The HI group included 18 patients and the NHI group included 308 patients. Median Injury Severity Score (ISS) in the HI group was 9. Injury sites included the chest, 2 (chest bruise, 1; tracheal injury, 1) and abdomen, 16 (hepatic injury, 6; pancreatic injury, 2; duodenal injury, 1; splenic injury, 1; small intestinal injury, 1; retroperitoneal hemorrhage, 1; renal injury, 1; abdominal wall musculature injury, 2; bladder injury, 1; and perineal laceration, 1). There were no significant differences in age, sex, ISS, and prognosis between the two groups. However, significant differences were seen in the abdominal median Abbreviated Injury Scale (AIS) score, which was higher in the HI group (3 vs 0, p < 0.01), and in the head median AIS score, which was higher in the NHI group (0 vs 2, p < 0.01). As mechanisms of injury, falling while riding a bicycle occurred significantly more frequently in the HI group (17 [94.4 %] vs 65 [21.1 %], p < 0.01). Direct transportation from the scene of the accident occurred significantly more often in the NHI group (5 [27.8 %] vs 255 [82.8 %], p < 0.01), whereas transfer from another hospital occurred significantly more frequently in the HI group (11 [61.1 %] vs 45 [14.6 %], p < 0.01). CONCLUSIONS: Handlebar injuries in children have significant potential to cause severe damage to visceral organs, especially those in the abdomen.

The clinical significance of circulating soluble RAGE in patients with severe sepsis.

BACKGROUND: The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor involved in the pathogenesis of inflammatory diseases. However, the significance of the soluble isoform of RAGE (sRAGE) has not been clarified in critical illness. We investigated circulating sRAGE in blood samples from septic patients. METHODS: In this cross-sectional study, criteria for inclusion were patients with severe sepsis and age older than 18 years. Samples were collected within 24 hours after the diagnosis of sepsis and also from healthy volunteers. The levels of sRAGE and RAGE signaling pathway-associated biologic parameters were measured with an enzyme-linked immunosorbent assay kit. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were calculated at the time of patient enrollment. We used the International Society of Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) diagnostic criteria algorithm to assess coagulopathy. RESULTS: Included were 24 septic patients and 12 healthy volunteers. Serum sRAGE level was significantly increased in the patients compared with healthy controls. Significant correlations were found between sRAGE levels and APACHE II, SOFA, and ISTH DIC scores. The increase in sRAGE levels also correlated with the upregulation of interleukin-6, soluble vascular adhesion molecule 1, and plasminogen activator inhibitor 1 levels and a reduction in platelet count. The fraction of sRAGE other than the endogenous secreted form of RAGE (esRAGE) was augmented in the patients. CONCLUSION: We demonstrated for the first time that the serum level of sRAGE increased with the progression of DIC and the severity of sepsis, suggesting that circulating sRAGE reflects RAGE signaling pathway activity, which induces the excessive inflammatory response involved in endothelial injury and coagulopathy and that its measurement may be useful as a biomarker for sepis. LEVEL OF EVIDENCE: Prognostic study, level IV.

Electrical vagus nerve stimulation attenuates systemic inflammation and improves survival in a rat heatstroke model.

This study was performed to gain insights into novel therapeutic approaches for the treatment of heatstroke. The central nervous system regulates peripheral immune responses via the vagus nerve, the primary neural component of the cholinergic anti-inflammatory pathway. Electrical vagus nerve stimulation (VNS) reportedly suppresses pro-inflammatory cytokine release in several models of inflammatory disease. Here, we evaluated whether electrical VNS attenuates severe heatstroke, which induces a systemic inflammatory response. Anesthetized rats were subjected to heat stress (41.5°C for 30 minutes) with/without electrical VNS. In the VNS-treated group, the cervical vagus nerve was stimulated with constant voltage (10 V, 2 ms, 5 Hz) for 20 minutes immediately after completion of heat stress. Sham-operated animals underwent the same procedure without stimulation under a normothermic condition. Seven-day mortality improved significantly in the VNS-treated group versus control group. Electrical VNS significantly suppressed induction of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in the serum 6 hours after heat stress. Simultaneously, the increase of soluble thrombomodulin and E-selectin following heat stress was also suppressed by VNS treatment, suggesting its protective effect on endothelium. Immunohistochemical analysis using tissue preparations obtained 6 hours after heat stress revealed that VNS treatment attenuated infiltration of inflammatory (CD11b-positive) cells in lung and spleen. Interestingly, most cells with increased CD11b positivity in response to heat stress did not express α7 nicotinic acetylcholine receptor in the spleen. These data indicate that electrical VNS modulated cholinergic anti-inflammatory pathway abnormalities induced by heat stress, and this protective effect was associated with improved mortality. These findings may provide a novel therapeutic strategy to combat severe heatstroke in the critical care setting.