Effects of rewarming therapies on outcomes in accidental hypothermia: A secondary analysis of a multicenter prospective study.

BACKGROUND: Rewarming therapies for accidental hypothermia (AH) include extracorporeal membrane oxygenation (ECMO) and non-ECMO related (conventional) therapies. However, there are limited data available to inform the selection of conventional rewarming therapy. The aim of the present study was to explore what patients' factors and which rewarming therapy predicted favorable prognosis. METHODS: This study is a secondary analysis of the Intensive Care with Extra Corporeal membrane oxygenation Rewarming in Accidentally Severe Hypothermia (ICE-CRASH) study, a multicenter prospective, observational study conducted in Japan. Enrolled in the ICE-CRASH study were patients aged ≥18 years with a core temperature of ≤32 °C who were transported to the emergency departments of 36 tertiary care hospitals in Japan between 1 December 2019 and 31 March 2022, among whom those who were rewarmed with conventional rewarming therapy were included in the present study. Logistic regression analysis was performed with 28-day survival as the objective variable; and seven factors including age, activities of daily living (ADL) independence, sequential organ failure assessment (SOFA) score, and each rewarming technique as explanatory variables. We performed linear regression analysis to identify whether each rewarming technique was associated with rewarming rate. RESULTS: Of the 499 patients enrolled in the ICE-CRASH study, 371 were eligible for this secondary analysis. The median age was 81 years, 50.9% were male, and the median initial body temperature was 28.8 °C. Age (odds ratio [OR]: 0.97, 95% confidence interval [CI]: 0.94-1.00) and SOFA score (OR: 0.73, 95% CI: 0.67-0.81) were associated with lower survival, whereas ADL independence (OR: 2.31, 95% CI: 1.15-4.63) was associated with higher survival. No conventional rewarming therapy was associated with 28-day survival. Hot bath was associated with a high rewarming rate (regression coefficient: 1.14, 95% CI: 0.75-1.53). CONCLUSION: No conventional rewarming therapy was associated with improved 28-day survival, which suggests that background factors such as age, ADL, and severity of condition contribute more to prognosis than does the selection of rewarming technique.

Hyperoxia for accidental hypothermia and increased mortality: a post-hoc analysis of a multicenter prospective observational study.

BACKGROUND: Supraphysiologic oxygen administration causes unfavorable clinical outcomes in various diseases, including traumatic brain injury, post-cardiac arrest syndrome, and acute lung injury. Accidental hypothermia is a critical illness that reduces oxygen demands, and excessive oxygen is likely to emerge. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with accidental hypothermia. METHODS: A post-hoc analysis of a nationwide multicenter prospective observational study (ICE-CRASH study) on patients with accidental hypothermia admitted in 2019-2022 was conducted. Adult patients without cardiac arrest whose core body temperature was < 32 °C and whose arterial partial pressure of oxygen (PaO2) was measured at the emergency department were included. Hyperoxia was defined as a PaO2 level of 300 mmHg or higher, and 28-day mortality was compared between patients with and without hyperoxia before rewarming. Inverse probability weighting (IPW) analyses with propensity scores were performed to adjust patient demographics, comorbidities, etiology and severity of hypothermia, hemodynamic status and laboratories on arrival, and institution characteristics. Subgroup analyses were conducted according to age, chronic cardiopulmonary diseases, hemodynamic instability, and severity of hypothermia. RESULTS: Of the 338 patients who were eligible for the study, 65 had hyperoxia before rewarming. Patients with hyperoxia had a higher 28-day mortality rate than those without (25 (39.1%) vs. 51 (19.5%); odds ratio (OR) 2.65 (95% confidence interval 1.47-4.78); p < 0.001). IPW analyses with propensity scores revealed similar results (adjusted OR 1.65 (1.14-2.38); p = 0.008). Subgroup analyses showed that hyperoxia was harmful in the elderly and those with cardiopulmonary diseases and severe hypothermia below 28 °C, whereas hyperoxia exposure had no effect on mortality in patients with hemodynamic instability on hospital arrival. CONCLUSIONS: Hyperoxia with PaO2 levels of 300 mmHg or higher before initiating rewarming was associated with increased 28-day mortality in patients with accidental hypothermia. The amount of oxygen to administer to patients with accidental hypothermia should be carefully determined. TRIAL REGISTRATION: The ICE-CRASH study was registered at the University Hospital Medical Information Network Clinical Trial Registry on April 1, 2019 (UMIN-CTR ID, UMIN000036132).

Soluble thrombomodulin ameliorates aberrant hemostasis after rewarming in a rat accidental hypothermia model.

BACKGROUND: Accidental hypothermia (AH) sometimes leads to coagulation disorder, especially in severe AH. We previously demonstrated that intrasplenic platelet activation caused aberrant hemostasis and thrombus formation after rewarming in a murine AH model. However, no study has focused on the appropriate management of platelets causing coagulation activation after rewarming of AH. We investigated whether or not recombinant soluble thrombomodulin (rTM) can suppress thrombosis formation after rewarming using a rat AH model. METHODS: Wistar rats were exposed to an ambient temperature of -20 °C under general anesthesia until their rectal temperature decreased to 26 °C. The Hypo group rats (n = 5) were immediately euthanized, while the Hypo/Re group (n = 5) and rTM group rats (n = 5), which were administered rTM (1 mg/kg) via the tail vein, were rewarmed until the rectal temperature returned to 34 °C and then euthanized 6 h later. Tissue and blood samples were collected from all rats for histopathological and coagulation analyses at euthanasia. RESULTS: There was no significant change in the D-dimer level in the Hypo group rats, while the D-dimer level was significantly elevated at 6 h after rewarming in the Hypo/Re group rats (P = 0.015), and histopathology detected both fibrin and platelets in the renal glomerulus. However, the rTM group rats did not show any elevation of the D-dimer levels at 6 h after rewarming, and no fibrin was noted on histopathology. CONCLUSIONS: rTM may be useful as an appropriate anticoagulant in cases of aberrant hemostasis after rewarming of AH.

Prognostic significance of skeletal muscle decrease in unresectable pancreatic cancer: Survival analysis using the Weibull exponential distribution model.

BACKGROUND/OBJECTIVES: Decrease in skeletal muscle mass and function is associated with a poor prognosis following surgical resection of pancreatic ductal adenocarcinomas (PDAs). This study evaluated whether skeletal muscle mass decrease affects PDA outcomes. METHODS: Data of 112 patients with advanced and unresectable PDA who underwent chemotherapy in a single institution were retrospectively analyzed. Information on age, sex, hematological investigations, including systemic inflammation-based markers and nutritional assessment biomarkers, and imaging parameters of skeletal muscle mass and visceral adipose tissue were retrieved from the patients' medical records. The efficiency of the Cox, Weibull, and standardized exponential models were compared using hazard ratios and the Akaike Information Criterion (AIC). RESULTS: Results from the Weibull, Cox, and standardized exponential model analyses indicated that low skeletal muscle mass, Eastern Cooperative Oncology Group performance status (PS), and the requirement of biliary drainage were associated with the highest risk of death, followed by carcinoembryonic antigen (CEA) levels and the presence of ascites. The AIC value from the four significant parameters was lowest for the Weibull-exponential distribution (222.3) than that of the Cox (653.7) and standardized exponential models (265.7). We developed a model for estimating the 1-year survival probability using the Weibull-exponential distribution. CONCLUSIONS: Low-skeletal muscle index, PS, requirement of biliary drainage, CEA levels, and presence of ascites are independent factors for predicting poor patient survival after chemotherapy. Improved survival modeling using a parametric approach may accurately predict the outcome of patients with advanced-stage PDA.

Polyphosphate, Derived from Lactobacillus brevis, Modulates the Intestinal Microbiome and Attenuates Acute Pancreatitis.

BACKGROUND: We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. AIMS: We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. METHODS: Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. RESULTS: The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. CONCLUSIONS: Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.

Accidental hypothermia: Factors related to a prolonged hospital stay - A nationwide observational study in Japan.

BACKGROUND: The incidence of accidental hypothermia (AH) is low, and the length of hospital stay in patients with AH remains poorly understood. The present study explored which factors were related to prolonged hospitalization among patients with AH using Japan's nationwide registry data. METHODS: The data from the Hypothermia STUDY 2018, which included patients ≥18 years old with a body temperature ≤ 35 °C, were obtained from a multicenter registry for AH conducted at 89 institutions throughout Japan, collected from December 1, 2018, to February 28, 2019. The patients were divided into a "short-stay patients" group (within 7 days) and "long-stay patients" group (more than 7 days). A logistic regression analysis after multiple imputation was performed to obtain odds ratios (ORs) for prolonged hospitalization with age, frailty, location, causes underlying the hypothermia, temperature, pH, potassium level, and disseminated intravascular coagulation (DIC) score as independent variables. RESULTS: In total, 656 patients were included in the study, of which 362 were eligible for the analysis. The median length of hospital stay was 17 days. Of the 362 patients, 265 (73.2%) stayed in the hospital for more than 7 days. The factors associated with prolonged hospitalization were frailty (OR, 2.11; 95% confidence interval [CI], 1.09-4.10; p = 0.027), the occurrence of indoor (OR, 3.20; 95% CI, 1.58-6.46; p = 0.001), alcohol intoxication (OR, 0.17; 95% CI, 0.05-0.56; p = 0.004), pH (OR, 0.07; 95% CI, 0.01-0.76; p = 0.029), potassium level (OR, 1.36; 95% CI, 1.00-1.85; p = 0.048), and DIC score (OR, 1.54; 95% CI, 1.13-2.10; p = 0.006). CONCLUSIONS: Frailty, indoor situation, alcohol intoxication, pH value, potassium level, and DIC score were factors contributing to prolonged hospitalization in patients with AH. Preventing frailty may help reduce the length of hospital stay in patients with AH. In addition, measuring the pH value and potassium level by an arterial blood gas analysis at the ED is recommended for the early evaluation of 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.

Low temperature induces von-willebrand factor expression via increased early growth response 1 transcriptional activity in splenic sinusoidal endothelial cells.

von Willebrand factor (vWF) is a large plasma glycoprotein that plays an important role in hemostasis by forming molecular bridges with platelets following vascular injury. Previously, we reported that hypothermia enhanced vWF production in the spleen, which resulted in the activation of the platelet pool in a hypothermia-induced murine model. However, the mechanisms that regulate vWF expression under hypothermic conditions remain unclear. In this study, we focused on vWF expression under hypothermic conditions in splenic endothelial cell culture. Human splenic endothelial cells (HSEC) were incubated at 20 °C for 1 h. Total RNA was extracted from the cells, and cDNA microarray gene expression analysis was performed. Genes that may be associated with vWF expression in low temperature culture conditions were then selected for further analysis. Gene expression analysis showed that low temperature conditions increased the expression of FOS and EGR1. We then hypothesized that these factors upregulate vWF mRNA expression in HSEC. The transcriptional inhibitors of EGR1 significantly inhibited vWF mRNA expression in HSEC cultured at a low temperature. Our analysis revealed that low temperatures enhance the gene expression of EGR1, which transcriptionally increases vWF expression. This acute-phase reaction may play an important role in platelet activation in the spleen during hypothermia.

A Nationwide Comparison Between Sepsis-2 and Sepsis-3 Definition in Japan.

BACKGROUND: Currently, it remains controversial whether the Sepsis-3 definition provides the most appropriate criteria for clinical use. The purpose of this study was to compare between the Sepsis-2 and Sepsis-3 definitions using Japan's nationwide registry. METHODS: Data were obtained from a multicenter registry conducted at 42 intensive care units (ICUs) throughout Japan, in which patients received treatment for severe sepsis or septic shock between January 2011 and December 2013. RESULTS: A total of 2797 patients diagnosed using the Sepsis-2 criteria were included in the present study. These patients were categorized into "Severe sepsis" (n = 1154) and "Sepsis-2 shock" (n = 1643) groups. Among the "Sepsis-2 shock" group, patients who did not meet the Sepsis-3 criteria for septic shock were categorized into the "Sepsis-2 shock-only" (n = 448, 27.3%) group, while patients who met the Sepsis-3 criteria for septic shock were categorized into "Sepsis-3 shock (n = 1195, 72.7%)" group. The ICU mortality in the "Sepsis-3 shock" group, "Sepsis-2 shock-only" group, and "Severe sepsis" group was 28.5%, 10.9%, and 14.1%, respectively. We observed no significant difference between the "Severe sepsis" and "Sepsis-2 shock-only" groups in terms of in-hospital survival (P = .098), while the "Sepsis-3 shock" group had the highest in-hospital mortality rate (P < .001). In a multivariate logistic regression analysis, liver insufficiency and immunocompromised status were independent prognostic factors in the "Sepsis-2 shock-only" group. In contrast, chronic heart disease and chronic hemodialysis were independent prognostic factors in the "Sepsis-3 shock" group. CONCLUSIONS: The ICU mortality of the "Sepsis-2 shock-only" group was significantly low. Besides septic shock diagnosed by the Sepsis-3 definition selects patients with more severe cases of sepsis among the "Sepsis-2 shock" group.

Low-dose immunoglobulin G is not associated with mortality in patients with sepsis and septic shock.

BACKGROUND: The administration of low-dose intravenous immunoglobulin G (IVIgG) (5 g/day for 3 days; approximate total 0.3 g/kg) is widely used as an adjunctive treatment for patients with sepsis in Japan, but its efficacy in the reduction of mortality has not been evaluated. We investigated whether the administration of low-dose IVIgG is associated with clinically important outcomes including intensive care unit (ICU) and in-hospital mortality. METHODS: This is a post-hoc subgroup analysis of data from a retrospective cohort study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study. The JSEPTIC DIC study was conducted in 42 ICUs in 40 institutions throughout Japan, and it investigated associations between sepsis-related coagulopathy, anticoagulation therapies, and clinical outcomes of 3195 adult patients with sepsis and septic shock admitted to ICUs from January 2011 through December 2013. To investigate associations between low-dose IVIgG administration and mortalities, propensity score-based matching analysis was used. RESULTS: IVIgG was administered to 960 patients (30.8%). Patients who received IVIgG were more severely ill than those who did not (Acute Physiology and Chronic Health Evaluation (APACHE) II score 24.2 ± 8.8 vs 22.6 ± 8.7, p < 0.001). They had higher ICU mortality (22.8% vs 17.4%, p < 0.001), but similar in-hospital mortality (34.4% vs 31.0%, p = 0.066). In propensity score-matched analysis, 653 pairs were created. Both ICU mortality and in-hospital mortality were similar between the two groups (21.0% vs 18.1%, p = 0.185, and 32.9% vs 28.6%, p = 0.093, respectively) using generalized estimating equations fitted with logistic regression models adjusted for other therapeutic interventions. The administration of IVIgG was not associated with ICU or in-hospital mortality (odds ratio (OR) 0.883; 95% confidence interval (CI) 0.655-1.192, p = 0.417, and OR 0.957, 95% CI, 0.724-1.265, p = 0.758, respectively). CONCLUSIONS: In this analysis of a large cohort of patients with sepsis and septic shock, the administration of low-dose IVIgG as an adjunctive therapy was not associated with a decrease in ICU or in-hospital mortality. TRIAL REGISTRATION: University Hospital Medical Information Network Individual Clinical Trials Registry, UMIN-CTR000012543 . Registered on 10 December 2013.

Variation in coagulation factor activity levels cause discrepancies between activated partial thromboplastin time and anti-Xa activity for heparin monitoring: a retrospective observational study.

BACKGROUND: Unfractionated heparin (UFH) is primarily monitored using activated partial thromboplastin time (APTT). However, the recent introduction of anti-activated factor X (anti-Xa) activity testing has provided a direct evaluation of Xa inhibition by anticoagulants. This study aimed to investigate discrepancies between APTT and anti-Xa activity during UFH monitoring in critically ill patients and explore their underlying causes. METHODS: This study analyzed 271 pairs of laboratory test results from blood samples of 99 critically ill patients receiving continuous intravenous UFH. Theoretical APTT values were calculated using fitted curve equations from spiked sample measurements with anti-Xa activity. Samples were categorized into three groups based on the measurement of the APTT/theoretical APTT ratio: the lower group (< 80%), the concordant group (80-120%), and the upper group (> 120%). RESULTS: The overall concordance rate between APTT and anti-Xa activity was 45%, with a 55% discrepancy rate. The lower group frequently showed apparent heparin overdoses, while coagulation factor activities in the lower and upper groups were higher and lower, respectively, than those in the concordant group. Particularly, the lower group exhibited higher factor VIII activity levels than the upper and concordant groups. CONCLUSIONS: Discrepancies between APTT and anti-Xa activity were frequently observed, influenced by changes in coagulation factors activity levels. The lower and upper groups were classified as pseudo-heparin-resistant and coagulopathy types, respectively. Accurate monitoring of heparin in critically ill patients is crucial, especially in cases of pseudo-heparin resistance, where APTT values may wrongly indicate inadequate heparin dosing despite sufficient anti-Xa activity. Understanding these discrepancies is important for managing heparin therapy in critically ill patients. TRIAL REGISTRATION: Not applicable.

Bioprotective role of platelet-derived microvesicles in hypothermia: Insight into the differential characteristics of peripheral and splenic platelets.

BACKGROUND: Most platelets are present in peripheral blood, but some are stored in the spleen. Because the tissue environments of peripheral blood vessels and the spleen are quite distinct, the properties of platelets present in each may also differ. However, no studies have addressed this difference. We previously reported that hypothermia activates splenic platelets, but not peripheral blood platelets, whose biological significance remains unknown. In this study, we focused on platelet-derived microvesicles (PDMVs) and analyzed their biological significance connected to intrasplenic platelet activation during hypothermia. METHODS: C57Bl/6 mice were placed in an environment of -20 °C, and their rectal temperature was decreased to 15 °C to model hypothermia. Platelets and skeletal muscle tissue were collected and analyzed for their interactions. RESULTS: Transcriptomic changes between splenic and peripheral platelets were greater in hypothermic mice than in normal mice. Electron microscopy and real-time RT-PCR analysis revealed that platelets activated in the spleen by hypothermia internalized transcripts, encoding tissue repairing proteins, into PDMVs and released them into the plasma. Plasma microvesicles from hypothermic mice promoted wound healing in the mouse myoblast cell line C2C12. Skeletal muscles in hypothermic mice were damaged but recovered within 24 h after rewarming. However, splenectomy delayed recovery from skeletal muscle injury after the mice were rewarmed. CONCLUSIONS: These results indicate that PDMVs released from activated platelets in the spleen play an important role in the repair of skeletal muscle damaged by hypothermia.

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.

Current status of active cooling, deep body temperature measurement, and face mask wearing in heat stroke and heat exhaustion patients in Japan: a nationwide observational study based on the Heatstroke STUDY 2020 and 2021.

Aim: The study aimed to determine the current status of face mask use, deep body temperature measurement, and active cooling in patients suffering from heat stroke and heat exhaustion in Japan. Methods: This was a prospective, observational, multicenter study using data from the Heatstroke STUDY 2020-2021, a nationwide periodical registry of heat stroke and heat exhaustion patients. Based on the Bouchama heatstroke criteria, we classified the patients into two groups: severe and mild-to-moderate. We compared the outcomes between the two groups and reclassified them into two subgroups according to the severity of the illness, deep body temperature measurements, and face mask use. Cramer's V was used to determine the effect sizes for a comparison between groups. Results: Almost all patients in this study were categorized as having degree III based on the Japanese Association for Acute Medicine heatstroke criteria (JAAM-HS). However, the severe group was significantly worse than the mild-to-moderate group in outcomes like in-hospital death and modified Rankin Scale scores, when discharged. Heat strokes had significantly higher rates of active cooling and lower mortality rates than heat stroke-like illnesses. Patients using face masks often use them during labor, sports, and other exertions, had less severe conditions, and were less likely to be young male individuals. Conclusions: It is suggested that severe cases require a more detailed classification of degree III in the JAAM-HS criteria, and not measuring deep body temperature could have been a factor in the nonperformance of active cooling and worse outcomes.

External validation of 5A score model for predicting in-hospital mortality among the accidental hypothermia patients: JAAM-Hypothermia study 2018-2019 secondary analysis.

BACKGROUND: The 5A score including five components "Age, Activities of daily living, Arrest, Acidemia and Albumin" was developed as an easy-to-use screening tool for predicting in-hospital mortality among patients with accidental hypothermia. However, the external validity of the 5A score has not yet been evaluated. We aimed to perform an external validation of the 5A score model. METHOD: This secondary analysis of the multicenter, prospective cohort Japanese Association for Acute Medicine-Hypothermia Study (2018-2019), which was conducted at 87 and 89 institutions throughout Japan, collected data from December 2018 to February 2019 and from December 2019 to February 2020. Adult accidental hypothermia patients whose body temperature was 35 °C or less were included in this analysis. The probability of in-hospital mortality was calculated using a logistic regression model of the 5A score. The albumin was not recorded in this database; thus, it was imputed by estimation. Predictions were compared with actual observations to evaluate the calibration of the model. Furthermore, decision-curve analysis was used to evaluate the clinical usefulness. RESULTS: Of the 1363 patients registered in the database, data of 1139 accidental hypothermia patients were included for analysis. The median [interquartile range] age was 79 [68-87] years, and there were 625 men (54.9%) in the study cohort. The predicted probability and actual observation by risk groups produced the following results: low 7% (5.4-8.6), mild 19.1% (17.4-20.8), moderate 33.2% (29.9-36.5), and high 61.9% (55.9-67.9) predicted risks, and the low 12.4% (60/483), mild 17.7% (59/334), moderate 32.6% (63/193), and high 69% (89/129) observed mortality. These results indicated that the model was well calibrated. Decision-curve analysis visually indicated the clinical utility of the 5A score model. CONCLUSION: This study indicated that the 5A score model using estimated albumin value has external validity in a completely different dataset from that used for the 5A model development. The 5A score is potentially helpful to predict the mortality risk and may be one of the valuable information for discussing the treatment strategy with patients and their family members.

Hypoxia-induced nuclear translocation of ß-catenin in the healing process of frostbite.

Frostbite occurs when the skin is exposed to localized low temperatures. The main causes of frostbite are thought to be direct cell injury due to freezing of cells and tissue ischemia due to abnormal blood circulation. However, the molecular mechanism of frostbite has not been elucidated. This study aims to explain the molecular dynamics of frostbite using a mouse frostbite model and keratinocyte cell culture. Comprehensive gene expression analysis performed on mouse skin samples revealed that ß-catenin signaling is activated by frostbite. Immunohistochemistry showed nuclear translocation of ß-catenin in the skin of frostbite model mice that was not observed in mice subjected to a mechanical skin damage model induced by tape stripping. Tissue hypoxia, as detected by pimonidazole staining, coexisted with nuclear expression of ß-catenin. In keratinocyte cell cultures, nuclear translocation of ß-catenin was induced by hypoxia, but not by low temperature. Hypoxia induced epithelial-mesenchymal transition - an important biological event in the healing process of skin - and in vitro wound-healing activity, both of which were suppressed by ß-catenin inhibition. Our results suggest that during frostbite, impaired blood flow causes hypoxia, which in turn activates ß-catenin that promotes keratinocyte motility and tissue repair.

Difference between 5A score and the HOPE score.

Recently, a letter to the editor was published to comment on the 5A score which is the prediction model for accidental hypothermia patients comparing the HOPE score. In this letter, we responded to the comments to clarify the difference between the 5A score and the HOPE score.

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.

Intensive care with extracorporeal membrane oxygenation rewarming in accident severe hypothermia (ICE-CRASH) study: a protocol for a multicentre prospective, observational study in Japan.

INTRODUCTION: Accidental hypothermia (AH) is a rare but critical disease, leading to death in severe cases. In recent decades, extracorporeal membrane oxygenation (ECMO) has been successfully used to rewarm hypothermic patients with cardiac arrest or circulation instability. However, data on the efficacy of rewarming using ECMO for patients with AH are limited. Therefore, a large-scale, multicentre, prospective study is warranted. The primary objective of this study will be to clarify the effectiveness of rewarming using ECMO for patients with AH. Our secondary objectives will be to compare the incidence of adverse effects between ECMO rewarming and non-ECMO rewarming and to identify the most appropriate management of ECMO for AH. METHODS AND ANALYSES: The Intensive Care with ExtraCorporeal membrane oxygenation Rewarming in Accidentally Severe Hypothermia study is taking place in 35 tertiary emergency medical facilities in Japan. The inclusion criteria are patients ≥18 years old with a body temperature ≤32°C. We will include patients with AH who present to the emergency department from December 2019 to March 2022. The research personnel at each hospital will collect several variables, including patient demographics, rewarming method, ECMO data and complications. Our primary outcome is to compare the 28-day survival rate between the ECMO and non-ECMO (other treatments) groups among patients with severe AH. Our secondary outcomes are to compare the following values between the ECMO and non-ECMO groups: length of stay in the intensive-care unit and complications. Furthermore, in patients with cardiac arrest, the Cerebral Performance Category score at discharge will be compared between both groups. ETHICS AND DISSEMINATION: This study received research ethics approval from Asahikawa Medical University (18194 and 19115). The study was approved by the institutional review board of each hospital, and the requirement for informed consent was waived due to the observational nature of the study. TRIAL REGISTRATION NUMBER: UMIN000036132.

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.