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Purpose Sex-based differences in post-traumatic mortality have been widely discussed for quite some time. We hypothesized that age-related pathophysiologic changes would affect sex-based differences in post-traumatic mortality and aimed to verify the hypothesis using a nationwide trauma registry in Japan. Methods This was a retrospective analysis of trauma patients registered in The Japanese Trauma Data Bank. We stratified the study population into the following three subsets based on age: (1) pediatric subset (age ≤ 14), (2) adult subset (age 15–50) and (3) senior adult subset (age ≥ 51). We evaluated both sex-based differences in mortality in each subset separately using multivariate logistic regression analysis and the two-way interaction effect for predicted survival between the continuous increase of age and the sexes using a nonlinear multivariate regression model. Results We included 122,819 trauma patients who fulfilled the inclusion criteria and classified them into the 3 subsets according to age. Male patients were more likely to die compared to female patients only in the senior adult subset (adjusted odds ratio: 1.26; 95% confidence interval: 1.18–1.36), whereas there were no statistically significant differences in the other two subsets. Furthermore, non-linear logistic regression analysis revealed that predicted survival probability in male patients decreased more sharply in accordance with the increase of age compared to that in female patients (p for interaction: 0.051). Conclusion Age-related change in post-traumatic mortality was significantly different between males and females, and male patients had a relatively higher risk of death in the older population.

Introduction The rapid increase of extended-spectrum beta-lactamase (ESBL)-producing pathogens makes it difficult to choose appropriate antimicrobials in patients with Gram-negative bacterial infection. The Cica-beta reagent (Kanto Chemical, Tokyo, Japan) is a chromogenic test that detects ESBLs from bacterial colonies. This study aimed to reveal whether Cica-beta reagent could detect ESBLs directly from urine samples to facilitate rapid diagnosis of antibiotic susceptibility. Methods A prospective study was conducted from July 2019 to November 2019. Patients in whom urine culture tests were performed were eligible. Each urine sample was centrifuged, and the pellet was mixed with Cica-beta reagent. The test was considered positive when the enzymatic reaction turned from yellow to red or orange. Results In total, 350 urine samples were analysed. Urinary tract infection (UTI) was diagnosed in 214 patients. ESBL-producing Enterobacterales were isolated from 79 samples. The Cica-beta test showed sensitivity of 79.8% and specificity of 99.3% in patients with Gram-negative bacteriuria. Sensitivity and specificity improved to 90.2% and 100%, respectively, in patients with UTI. Conclusion The Cica-beta test could be an efficient test for the detection of ESBL-producing pathogens in urine. By providing immediate information about ESBLs, it might be a useful point-of-care test to guide appropriate antimicrobial use in patients with UTI.

Objectives: One of the most significant features of poor prognosis in COVID-19 is pulmonary fibrosis. Nintedanib is a new antifibrotic agent that interferes with processes of pulmonary fibrosis. This study aimed to investigate the efficacy and safety of nintedanib in COVID-19. Methods: This was an interventional study in which adult patients with COVID-19 requiring mechanical ventilation were consecutively enrolled. The primary endpoint was 28-day mortality after the initiation of mechanical ventilation. The secondary endpoints were length of mechanical ventilation, volume of lung injury, and the incidence of gastrointestinal adverse events and acute liver failure. Results: Thirty patients with COVID-19 underwent nintedanib therapy. We included 30 patients not receiving nintedanib as the historical control group. There were no significant differences in 28-day mortality between the groups (23.3% vs 20%, P = 0.834). Lengths of mechanical ventilation were significantly shorter in the nintedanib group (P = 0.046). Computed tomography volumetry showed that the percentages of high-attenuation areas were significantly lower in the nintedanib group at liberation from mechanical ventilation (38.7% vs 25.7%, P = 0.027). There were no significant differences in the adverse events. Conclusions: The administration of nintedanib may offer potential benefits for minimizing lung injury in COVID-19.

Background There is no one-size-fits-all empiric antimicrobial therapy for sepsis because the pathogens vary according to the site of infection and have changed over time. Therefore, updating knowledge on the spectrum of pathogens is necessary for the rapid administration of appropriate antimicrobials. Objective The aim of this study was to elucidate the current spectrum of pathogens and its variation by site of infection in sepsis. Methods This was a prospective nationwide cohort study of consecutive adult patients with sepsis in 59 intensive care units in Japan. The spectrum of pathogens was evaluated in all patients and in subgroups by site of infection. Regression analyses were conducted to evaluate the associations between the pathogens and mortality. Results The study cohort comprised 1184 patients. The most common pathogen was Escherichia coli (21.5%), followed by Klebsiella pneumoniae (9.0%). However, the pattern varied widely by site of infection; for example, gram-positive bacteria were the dominant pathogen in bone/soft tissue infection (55.7%) and cardiovascular infection (52.6%), but were rarely identified in urinary tract infection (6.4%). In contrast, gram-negative bacteria were the predominant pathogens in abdominal infection (38.4%) and urinary tract infection (72.0%). The highest mortality of 47.5% was observed in patients infected with methicillin-resistant Staphylococcus aureus, which was significantly associated with an increased risk of death (odds ratio 1.88, 95% confidence interval 1.22–2.91). Conclusions This study revealed the current spectrum of pathogens and its variation based on the site of infection, which is essential for empiric antimicrobial therapy against sepsis.

Background There have been no clinical studies to sufficiently reveal the interaction effect generated by combinations of injury regions of multiple injuries. We hypothesized that certain combinations of trauma regions might lead to increased risk of traumatic death and aimed to verify this hypothesis using a nationwide trauma registry in Japan. Materials and methods This was a retrospective study of trauma patients registered in the Japan Trauma Data Bank between 2004 and 2017. We included patients who suffered blunt trauma with an Injury Severity Score of 16 or more. The trauma was classified into four regions (head, chest, abdomen, and extremities), and a multivariable logistic regression analysis was performed that included interaction terms derived from the combination of two regions as covariates. Results We included 78,280 trauma patients in this study. Among them, 16,100 (20.6%) patients were discharged to death. Multivariable logistic regression showed the odds ratio (OR) of in-hospital death compared with patients without injury of an Abbreviated Injury Scale score of 3 or more in each injured region as follows: head score, 2.31 (95% confidence interval [CI], 2.13-2.51); chest score, 2.28 (95% CI, 2.17-2.39); abdomen score, 1.68 (95% CI, 1.56-1.82); and extremities score, 1.84 (95% CI, 1.76-1.93), respectively. In addition, the ORs of the statistically significant interaction terms were as follows: head-chest 1.29 (95% CI, 1.13-1.48), chest-abdomen 0.77 (95% CI, 0.67-0.88), chest-extremities 1.95 (95% CI, 1.77-2.14), and abdomen-extremities 0.70 (95% CI, 0.62-0.79), respectively. Conclusion In this population, among patients with multiple injuries, a combination of head-chest trauma and chest-extremities trauma was shown to increase the risk of traumatic death. Level of evidence Prognostic, Level III.

Multiple organ dysfunction syndrome (MODS) is a predominant cause of death in acute respiratory distress syndrome (ARDS). Disseminated intravascular coagulation (DIC) is recognized as a syndrome that frequently develops MODS. To test the hypothesis that DIC scores are useful for predicting MODS development and that DIC is associated with MODS, we retrospectively analyzed the data of a prospective, multicenter study on ARDS.Patients who met the Berlin definition of ARDS were included. DIC scores as well as the disease severity and the development of MODS on the day of the diagnosis of ARDS (day 0) and day 3 were evaluated. The primary and secondary outcomes were the development of MODS and the hospital mortality.In the 129 eligible patients, the prevalence of DIC was 45.7% (59/129). DIC patients were more seriously ill and exhibited a higher prevalence of MODS on days 0 and 3 than non-DIC patients. The DIC scores on day 0 detected the development of MODS with good area under the receiver operating characteristic curve (0.714, p.001). DIC on day 0 was significantly associated with MODS on days 0 and 3 (odds ratio 1.53 and 1.34, respectively). Patients with persistent DIC from days 0 to 3 had higher rates of both MODS on day 3 (p=.035) and hospital mortality (p=.031) than the other patients.DIC scores were able to predict MODS, and DIC was associated with MODS during the early stage of ARDS. Persistent DIC may also have role in this association.

Background Elderly patients have a blunted host response, which may influence vital signs and clinical outcomes of sepsis. This study was aimed to investigate whether the associations between the vital signs and mortality are different in elderly and non-elderly patients with sepsis. Methods This was a retrospective observational study. A Japanese multicenter sepsis cohort (FORECAST, n = 1148) was used for the discovery analyses. Significant discovery results were tested for replication using two validation cohorts of sepsis (JAAMSR, Japan, n = 624; SPH, Canada, n = 1004). Patients were categorized into elderly and non-elderly groups (age ≥ 75 or Results In the discovery cohort, non-elderly patients with BT P = 0.025, adjusted hazard ratio 1.70, 95% CI 1.07–2.71). In the validation cohorts, non-elderly patients with BT P = 0.0024, adjusted hazard ratio 2.05, 95% CI 1.29–3.26; SPH, P = 0.029, adjusted hazard ratio 1.36, 95% CI 1.03–1.80). These differences were not observed in elderly patients in the three cohorts. Associations between the other four vital signs and mortality were not different in elderly and non-elderly patients. The interaction of age and hypothermia/fever was significant (P Conclusions In septic patients, we found mortality in non-elderly sepsis patients was increased with hypothermia and decreased with fever. However, mortality in elderly patients was not associated with BT. These results illuminate the difference in the inflammatory response of the elderly compared to non-elderly sepsis patients.

Background Diagnosing sepsis remains difficult because it is not a single disease but a syndrome with various pathogen- and host factor-associated symptoms. Sepsis-3 was established to improve risk stratification among patients with infection based on organ failures, but it has been still controversial compared with previous definitions. Therefore, we aimed to describe characteristics of patients who met sepsis-2 (severe sepsis) and sepsis-3 definitions. Methods This was a multicenter, prospective cohort study conducted by 22 intensive care units (ICUs) in Japan. Adult patients (≥ 16 years) with newly suspected infection from December 2017 to May 2018 were included. Those without infection at final diagnosis were excluded. Patient’s characteristics and outcomes were described according to whether they met each definition or not. Results In total, 618 patients with suspected infection were admitted to 22 ICUs during the study, of whom 530 (85.8%) met the sepsis-2 definition and 569 (92.1%) met the sepsis-3 definition. The two groups comprised different individuals, and 501 (81.1%) patients met both definitions. In-hospital mortality of study population was 19.1%. In-hospital mortality among patients with sepsis-2 and sepsis-3 patients was comparable (21.7% and 19.8%, respectively). Patients exclusively identified with sepsis-2 or sepsis-3 had a lower mortality (17.2% vs. 4.4%, respectively). No patients died if they did not meet any definitions. Patients who met sepsis-3 shock definition had higher in-hospital mortality than those who met sepsis-2 shock definition. Conclusions Most patients with infection admitted to ICU meet sepsis-2 and sepsis-3 criteria. However, in-hospital mortality did not occur if patients did not meet any criteria. Better criteria might be developed by better selection and combination of elements in both definitions. Trial registration UMIN000027452

The clinical implications of bacteremia among septic patients remain unclear, although a vast amount of data have been accumulated on sepsis. We aimed to compare the clinical characteristics and outcomes of severe sepsis patients with and without bacteremia. This secondary analysis of a multicenter, prospective cohort study included 59 intensive care units (ICUs) in Japan between January 2016 and March 2017. The study cohort comprised 1,184 adults (aged ≥ 16 years) who were admitted to an ICU with severe sepsis and diagnosed according to the Sepsis-2 criteria. Of 1,167 patients included in the analysis, 636 (54.5%) had bacteremia. Those with bacteremia had significantly higher rates of septic shock (66.4% vs. 58.9%, p = 0.01) and higher sepsis severity scores, including the Acute Physiology and Chronic Health Evaluation (APACHE) II and the Sequential Organ Failure Assessment (SOFA). No significant difference in in-hospital mortality was seen between patients with and without bacteremia (25.6% vs. 21.0%, p = 0.08). In conclusion, half of severe sepsis patients in ICUs have bacteremia. Although patients with bacteremia had more severe state, between-group differences in patient-centered outcomes, such as in-hospital mortality, have not been fully elucidated.

In planned planetary explorations, cryogenic liquids such as liquid hydrogen (LH2), liquid oxygen (LOX), and liquefied natural gases (LNG) are used as fuel and oxidants in the propulsion systems of spacecraft. Such explorations require long-term storage for those cryogens, as well as heat insulation technology to protect the heat from the outside and pressure control technology to suppress rises in pressure due to evaporation gas in the propellant tank. However, current vent systems that discharge the evaporated gas to the outside of the spacecraft are suboptimal, for the propellant’s uncertain position in the tank when spacecraft operate in microgravity environments causes the significant loss of propellant during venting. In response, we examined a method using jet mixing in a thermodynamic vent system (TVS) that adjusts the tank pressure by cooling the inside of the tank and reducing boil-off gas. To that end, thermal and fluid analyses were conducted to design a test tank system before the ground verification test of the TVS using liquid nitrogen (LN2) as the simulated cryogen. To evaluate our results, we compared experimental and numerical results regarding the formation of thermal stratification. The experimentally performed verification of the TVS function revealed that jet mixing can lower the liquid’s temperature in the tank after the experimental apparatus was modified to supply a stable subcooled mixing jet.

Background The updated Surviving Sepsis Campaign guidelines recommend a 1-hour window for completion of a sepsis care bundle; however, the effectiveness of the hour-1 bundle has not been fully evaluated. The present study aimed to evaluate the impact of hour-1 bundle completion on clinical outcomes in sepsis patients. Methods This was a multicenter, prospective, observational study conducted in 17 intensive care units in tertiary hospitals in Japan. We included all adult patients who were diagnosed as having sepsis by Sepsis-3 and admitted to intensive care units from July 2019 to August 2020. Impacts of hour-1 bundle adherence and delay of adherence on risk-adjusted in-hospital mortality were estimated by multivariable logistic regression analyses. Results The final study cohort included 178 patients with sepsis. Among them, 89 received bundle-adherent care. Completion rates of each component (measure lactate level, obtain blood cultures, administer broad-spectrum antibiotics, administer crystalloid, apply vasopressors) within 1 hour were 98.9%, 86.2%, 51.1%, 94.9%, and 69.1%, respectively. Completion rate of all components within 1 hour was 50%. In-hospital mortality was 18.0% in the patients with and 30.3% in the patients without bundle-adherent care (p = 0.054). The adjusted odds ratio of non-bundle-adherent versus bundle-adherent care for in-hospital mortality was 2.32 (95% CI 1.09–4.95) using propensity scoring. Non-adherence to obtaining blood cultures and administering broad-spectrum antibiotics within 1 hour was related to in-hospital mortality (2.65 [95% CI 1.25–5.62] and 4.81 [95% CI 1.38–16.72], respectively). The adjusted odds ratio for 1-hour delay in achieving hour-1 bundle components for in-hospital mortality was 1.28 (95% CI 1.04–1.57) by logistic regression analysis. Conclusion Completion of the hour-1 bundle was associated with lower in-hospital mortality. Obtaining blood cultures and administering antibiotics within 1 hour may have been the components most contributing to decreased in-hospital mortality.

Disseminated intravascular coagulation (DIC) is one of the major organ dysfunctions associated with sepsis. This retrospective secondary analysis comprised data from a prospective multicenter study to investigate the age-related differences in the survival benefit of anticoagulant therapy in sepsis according to the DIC diagnostic criteria. Adult patients with severe sepsis based on the Sepsis-2 criteria were enrolled and divided into the following groups: (1) anticoagulant group (patients who received anticoagulant therapy) and (2) non-anticoagulant group (patients who did not receive anticoagulant therapy). Patients in the former group were administered antithrombin, recombinant human thrombomodulin, and their combination. The multivariate Cox proportional hazard regression model showed that the risk increases were suppressed in the high-DIC-score patients aged 60–70 years receiving anticoagulant therapy. No favorable association of anti-coagulant therapy with hospital mortality was observed in patients aged 50 years and 80 years. Furthermore, anticoagulant therapy in the lower-DIC-score range increased the risk in patients aged 50–60 years. In conclusion, anticoagulant therapy was associated with decreased hospital mortality according to a higher DIC score in septic patients aged 60–70 years. Anticoagulant therapy, however, was not associated with a better outcome in relatively younger and older patients with sepsis.

Background: Traumatic brain injury (TBI)-associated coagulopathy is a widely recognized risk factor for secondary brain damage and contributes to poor clinical outcomes. Various theories, including disseminated intravascular coagulation (DIC), have been proposed regarding its pathomechanisms; no consensus has been reached thus far. This study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing coagulofibrinolytic changes in isolated TBI (iTBI) to those in non-TBI, to determine the associated factors, and identify the clinical significance of DIC diagnosis in patients with iTBI.Methods: This secondary multicenter, prospective study assessed patients with severe trauma. iTBI was defined as Abbreviated Injury Scale (AIS) scores ≥4 in the head and neck, and ≤2 in other body parts. Non-TBI was defined as AIS scores ≥4 in single body parts other than the head and neck, and the absence of AIS scores ≥3 in any other trauma-affected parts. Specific biomarkers for thrombin and plasmin generation, anticoagulation, and fibrinolysis inhibition were measured at the presentation to the emergency department (0 h) and 3 h after arrival.Results: We analyzed 34 iTBI and 40 non-TBI patients. Baseline characteristics, transfusion requirements and in-hospital mortality did not significantly differ between groups. The changes in coagulation/fibrinolysis-related biomarkers were similar. Lactate levels in the iTBI group positively correlated with DIC scores (rho = −0.441, p = 0.017), but not with blood pressure (rho = −0.098, p = 0.614). Multiple logistic regression analyses revealed that the injury severity score was an independent predictor of DIC development in patients with iTBI (odds ratio = 1.237, p = 0.018). Patients with iTBI were further subdivided into two groups: DIC (n = 15) and non-DIC (n = 19) groups. Marked thrombin and plasmin generation were observed in all patients with iTBI, especially those with DIC. Patients with iTBI and DIC had higher requirements for massive transfusion and emergency surgery, and higher in-hospital mortality than those without DIC. Furthermore, DIC development significantly correlated with poor hospital survival; DIC scores at 0 h were predictive of in-hospital mortality.Conclusions: Coagulofibrinolytic changes in iTBI and non-TBI patients were identical, and consistent with the pathophysiology of DIC. DIC diagnosis in the early phase of TBI is key in predicting the outcomes of severe TBI.

Background: The Sequential Organ Failure Assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction in sepsis and is definitely proved to be associated with mortality. However, differences in prognostic value between SOFA subscores have not been sufficiently evaluated so far, and detailed evaluation of subscores is required to verify the clinical significance of the SOFA score. The present study aimed to evaluate the non-linear prognostic association of SOFA subscores and the cross-interaction effects on mortality when SOFA subscores were simultaneously increased.Methods: This retrospective observational study used a part of a large-scale database containing about 30 million patients. Among them, we included all adult patients requiring unplanned hospital admission and were diagnosed as having sepsis by Sepsis-3 criteria from February 2006 to December 2019. A proven/suspected infection was defined as having any of the ICD-10 codes for infection. Associations between the SOFA components and in-hospital mortality were examined using linear and non-linear logistic regression analyses. We also evaluated two-way interaction effects on mortality between an increase of one SOFA subscore and another.Results: The final study cohort included 38,869 patients with sepsis. Restricted cubic spline analyses showed that an increase in total SOFA score was sharply and linearly associated with increased mortality. However, the prognostic association of SOFA subscores was non-linear and varied widely by biomarker: platelet count showed a J-shaped association, creatinine showed an inverted J-shaped association, and bilirubin showed only a weak association with mortality. The mortality odds ratios of SOFA scores were synergistically increased when another SOFA subscore was higher than 2 points, and the effect modifications were statistically significant in almost all subgroups. Especially in patients with cardiovascular or hepatic subscores of ≥ 2 points, odds ratios of the other SOFA subscores were remarkably increased (double to triple) compared to those in the whole study population.Conclusion: Despite the widely varied prognostic associations of SOFA subscores, total SOFA score was sharply and almost linearly associated with increased mortality. Cross-interactions between subscores synergistically enhanced its prognostic associations and might be responsible for the high prognostic accuracy of the total SOFA score.

Background Trends in the incidence and outcomes of sepsis using a Japanese nationwide database were investigated. Methods This was a retrospective cohort study. Adult patients, who had both presumed serious infections and acute organ dysfunction, between 2010 and 2017 were extracted using a combined method of administrative and electronic health record data from the Japanese nationwide medical claim database, which covered 71.5% of all acute care hospitals in 2017. Presumed serious infection was defined using blood culture test records and antibiotic administration. Acute organ dysfunction was defined using records of diagnosis according to the international statistical classification of diseases and related health problems, 10th revision, and records of organ support. The primary outcomes were the annual incidence of sepsis and death in sepsis per 1000 inpatients. The secondary outcomes were in-hospital mortality rate and length of hospital stay in patients with sepsis. Results The analyzed dataset included 50,490,128 adult inpatients admitted between 2010 and 2017. Of these, 2,043,073 (4.0%) patients had sepsis. During the 8-year period, the annual proportion of patients with sepsis across inpatients significantly increased (slope = + 0.30%/year, P P = 0.0001), accounting for 7.8 deaths per 1000 inpatients in 2017. The in-hospital mortality rate and median (interquartile range) length of hospital stay significantly decreased (P Conclusions The Japanese nationwide data indicate that the annual incidence of sepsis and death in inpatients with sepsis significantly increased; however, the annual mortality rates and length of hospital stay in patients with sepsis significantly decreased. The increasing incidence of sepsis and death in sepsis appear to be a significant and ongoing issue.

This study aimed to assess the value of quick sequential organ failure assessment (qSOFA) combined with other risk factors in predicting in-hospital mortality in patients presenting to the emergency department with suspected infection. This post-hoc analysis of a prospective multicenter study dataset included 34 emergency departments across Japan (December 2017 to February 2018). We included adult patients (age ≥16 years) who presented to the emergency department with suspected infection. qSOFA was calculated and recorded by senior emergency physicians when they suspected an infection. Different types of sepsis-related risk factors (demographic, functional, and laboratory values) were chosen from prior studies. A logistic regression model was used to assess the predictive value of qSOFA for in-hospital mortality in models based on the following combination of predictors: 1) qSOFA-Only; 2) qSOFA+Age; 3) qSOFA+Clinical Frailty Scale (CFS); 4) qSOFA+Charlson Comorbidity Index (CCI); 5) qSOFA+lactate levels; 6) qSOFA+Age+CCI+CFS+lactate levels. We calculated the area under the receiver operating characteristic curve (AUC) and other key clinical statistics at Youden’s index, where the sum of sensitivity and specificity is maximized. Following prior literature, an AUC >0.9 was deemed to indicate high accuracy; 0.7–0.9, moderate accuracy; 0.5–0.7, low accuracy; and 0.5, a chance result. Of the 951 patients included in the analysis, 151 (15.9%) died during hospitalization. The AUC for predicting in-hospital mortality was 0.627 (95% confidence interval [CI]: 0.580−0.673) for the qSOFA-Only model. Addition of other variables only marginally improved the model’s AUC; the model that included all potentially relevant variables yielded an AUC of only 0.730 (95% CI: 0.687–0.774). Other key statistic values were similar among all models, with sensitivity and specificity of 0.55−0.65 and 0.60−0.75, respectively. In this post-hoc data analysis from a prospective multicenter study based in Japan, combining qSOFA with other sepsis-related risk factors only marginally improved the model’s predictive value.

Background: Disseminated intravascular coagulation (DIC) commonly complicates sepsis and considerably worsens mortality. Recent studies suggested that anticoagulant therapies improved mortality only in specific sepsis populations, and key pathologies for selecting optimal targets needed to be identified. Anticoagulant activities were naturally altered with aging. This study aimed to evaluate age-related differences in efficacy of anticoagulant therapies in sepsis.Methods: This post hoc analysis of a nationwide multicenter cohort study was conducted in 42 intensive care units in Japan. Adult patients with septic DIC were divided into anticoagulant and control groups. Age-related changes in predicted mortality in both groups were compared using a logistic regression model including two-way interaction terms. Patients were also stratified into three subsets based on age, and propensity score-adjusted Cox regression analyses were conducted to examine survival effect of anticoagulants in each subset.Results: We included 1432 patients with septic DIC; 867 patients received anticoagulants and 565 received none. Age-related change in predicted mortality was significantly different between groups (p for interaction = 0.013), and the gap between groups was broad in the younger population. Similarly, in Cox regression analyses, anticoagulant therapies were associated with significantly lower mortality in the subsets of age ≤60 and 60-79 (hazard ratios = 0.461, 0.617, p = 0.007, 0.005, respectively), whereas there was no difference in survival between the groups in the subsets of age ≥80.Conclusion: The efficacy of anticoagulant therapies for septic DIC might be associated with patient age.

Purpose Posttraumatic meningitis is one of the severe complications that can result in increased mortality and longer hospital stay among trauma patients. Factors such as cerebrospinal fluid (CSF) fistula and basilar skull fracture are associated with posttraumatic meningitis. However, it remains unclear whether procedures such as burr hole surgery in the emergency department and decompressive craniectomy are associated with posttraumatic meningitis. The aim of this study was to assess factors associated with posttraumatic meningitis with a nationwide hospital-based trauma registry in Japan. Methods This was a retrospective observational study with a 12-year study period from January 2004 to December 2015. We included trauma patients registered in the Japanese Trauma Data Bank, whose head Abbreviated Injury Scale score was ≥ 3 in this study. The main endpoint was the occurrence of meningitis during hospitalization. Multivariable logistic regression analysis was used to assess independent parameters associated with posttraumatic meningitis such as CSF fistula, burr hole surgery in the emergency department, and decompressive craniectomy. Results Among 60,390 head injury patients with head AIS score 3 or more, 284 (0.5%) patients had posttraumatic meningitis. Factors associated with posttraumatic meningitis were burr hole surgery in the emergency department (adjusted odds ratio [AOR] 2.158 [95% confidence interval (CI) 1.401–3.325]), decompressive craniectomy (AOR 2.123 [95% CI 1.506–2.993]), external ventricular drainage (AOR 1.843 [95% CI, 1.157–2.935]), CSF leakage (AOR 3.328 [95% CI 2.205–5.022]), and basilar skull fracture (AOR 1.651 [95% CI 1.178–2.314]). Conclusions In this population of trauma patients, burr hole surgery in the emergency department and decompressive craniectomy was associated with posttraumatic meningitis.

Background Anticoagulant therapy has seldom been achieved in randomized trials targeting nonspecific overall sepsis patients. Although the key components to identify the appropriate target in sepsis may be disseminated intravascular coagulation (DIC) and high disease severity, the interaction and relation of these two components for the effectiveness of therapy remain unknown. Objective This article identifies the optimal target of anticoagulant therapy in sepsis. Methods We used a prospective nationwide cohort targeting consecutive adult severe sepsis patients in 59 intensive care units in Japan to assess associations between anticoagulant therapy and in-hospital mortality according to DIC (International Society on Thrombosis and Haemostasis [ISTH] overt and Japanese Association for Acute Medicine DIC scores) and disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] and Sequential Organ Failure Assessment scores). Multivariable Cox proportional hazard regression analysis with nonlinear restricted cubic spline including a two-way interaction term (treatment × each score) and three-way interaction term (treatment × ISTH overt DIC score × APACHE II score) was performed. Results The final study cohort comprised 1,178 sepsis patients (371 received anticoagulants and 768 did not). The regression model including the two-way interaction term showed significant interaction between intervention and disease severity as indicated by the ISTH overt DIC score and APACHE II score (p = 0.046 and p = 0.101, respectively). Three-way interaction analysis revealed that risk hazard was suppressed in the anticoagulant group compared with the control group in the most severe subset of both scores. Conclusion Anticoagulant therapy was associated with better outcome according to the deterioration of both DIC and disease severity, suggesting that anticoagulant therapy should be restricted to patients having DIC and high disease severity simultaneously.

Purpose Hospital services are reduced during off-hour such as nighttime or weekend. Investigations of the off-hour effect on initial management and outcomes in sepsis are very limited. Thus, we tested the hypothesis that patients who were diagnosed with severe sepsis during the nighttime or on non-business days had altered initial management and clinical outcomes. Materials and methods Patients with severe sepsis from 59 ICUs between 2016 and 2017 were enrolled. The patients were categorized according to the diagnosis time or day and were then compared. The primary outcome was in-hospital mortality. Results One thousand one hundred and forty-eight patients were analyzed; 769 daytime patients, vs. 379 nighttime patients, and 791 business day patients vs. 357 non-business day patients. There were no significant differences in in-hospital mortality between either daytime and nighttime (24.4% vs. 21.4%, P = .27; nighttime, adjusted odds ratio [OR] 1.17, 95% confidence interval [CI], 0.87–1.59, P = .30) or between business and non-business days (22.9% vs. 24.6%, P = .55; non-business day, adjusted OR 0.85, 95% CI 0.60–1.22, P = .85). Time to antibiotics was significantly shorter in the nighttime (114 vs. 89 min, P = .0055). Conclusions Nighttime and weekends were not associated with increased in-hospital mortality of severe sepsis.

Disseminated intravascular coagulation (DIC) is a frequent complication in sepsis. Once patients develop DIC, the mortality rate increases significantly. Moreover, recent studies have suggested that coagulation disorder plays a significant role in the development of organ dysfunction in sepsis. Thus, the early detection of DIC is vital in sepsis care, and the Japanese Association for Acute Medicine established a set of original diagnostic criteria in 2006 (JAAM DIC). Since then, the usefulness of the JAAM DIC has been repeatedly reported, and these criteria have been widely adopted in emergency and critical care settings in Japan. Different criteria have also been released by the International Society on Thrombosis and Haemostasis (ISTH overt-DIC), and the latter criteria are presently considered to be the international standard. Compared with the JAAM DIC, the ISTH overt-DIC criteria are stricter and the timing of diagnosis is later. This discrepancy is because of conceptual differences. As many physicians think sepsis-associated DIC is the target of anticoagulant therapies in Japan, the JAAM DIC criteria were designed to allow the early initiation of treatment. As other countries do not provide DIC-specific treatments, early diagnosis is not necessary, and this situation has led to a significant gap. However, as overt-DIC is a late-phase coagulation disorder, a need for early detection has been advocated, and members of the ISTH have recently proposed the category of sepsis-induced coagulopathy. In this review, we introduce the strengths and weaknesses of the major criteria including JAAM-DIC, ISTH overt-DIC, sepsis-induced coagulopathy, and Japanese Society on Thrombosis and Haemostasis-DIC.

Background Early and accurate diagnosis of sepsis is challenging. Although procalcitonin and presepsin have been identified as potential biomarkers to differentiate between sepsis and other non-infectious causes of systemic inflammation, the diagnostic accuracy of these biomarkers remains controversial. Herein, we performed a comprehensive meta-analysis to assess the overall diagnostic value of procalcitonin and presepsin for the diagnosis of sepsis. Methods We searched three electronic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) for relevant studies. Two authors independently screened articles on the basis of inclusion and exclusion criteria. The pooled sensitivity, specificity, and summary receiver operating characteristic curves were estimated. The quality of evidence for diagnostic accuracy in absolute effects, i.e., the number of true or false positives and true or false negatives, gave a particular pre-test probability. Results We included 19 studies (19 observational studies and no randomized controlled trials) that had enrolled 3012 patients. Analyses of summary receiver operating characteristic curves revealed areas under the receiver operating characteristic curves of 0.84 for procalcitonin and 0.87 for presepsin. The pooled sensitivities and specificities were 0.80 (95% confidence interval 0.75 to 0.84) and 0.75 (95% confidence interval 0.67 to 0.81) for procalcitonin. For presepsin, these values were 0.84 (95% confidence interval 0.80 to 0.88) and 0.73 (95% confidence interval 0.61 to 0.82), respectively. There were no statistically significant differences in both pooled sensitivities (p = 0.48) and specificities (p = 0.57) between procalcitonin and presepsin. Conclusion Our meta-analysis provided evidence that the diagnostic accuracy of procalcitonin and presepsin in detecting infection was similar and that both are useful for early diagnosis of sepsis and subsequent reduction of mortality in critically ill adult patients. Systematic review registration The study was registered in PROSPERO under the registration number CRD42016035784. Electronic supplementary material The online version of this article (10.1186/s40560-019-0374-4) contains supplementary material, which is available to authorized users.

Accepted: 2018-05-21, 資料番号: SA1180213000

The diagnostic criteria of overt disseminated intravascular coagulation (DIC) were established by the International Society on Thrombosis and Haemostasis (ISTH) in 2001. Since then, DIC has long been associated with adverse outcomes. However, recent advances in sepsis shed light on the role of coagulation disorders in the progression of sepsis. Currently, inflammation and coagulation are recognized as the two drivers that promote organ dysfunction in sepsis and septic shock. The ISTH has published new diagnostic criteria for improved management, namely sepsis-induced coagulopathy (SIC), in 2017. SIC is a pragmatic scoring system composed of platelet count, prothrombin time, and organ dysfunction score to detect the early-stage of sepsis-associated DIC. Since overt DIC represents an uncompensated coagulation disorder, a two-step approach using SIC and overt DIC criteria is a novel strategy to evaluate the severity and manage this challenging complication. Although there is no globally agreed on anticoagulant therapy for DIC, the Japanese Surviving Sepsis Campaign Guidelines 2020 recommend using antithrombin and recombinant thrombomodulin for sepsis associated DIC. Since research in this area has been previously reported, an international collaborative study is necessary to develop future diagnostic tools and treatment strategies.

Glycemic control strategies for sepsis have changed significantly over the last decade, but their impact on dysglycemia and its associated outcomes has been poorly understood. In addition, there is controversy regarding the detrimental effects of hyperglycemia in sepsis. To evaluate the incidence and risks of dysglycemia under current strategy, we conducted a preplanned subanalysis of the sepsis cohort in a prospective, multicenter FORECAST study. A total of 1,140 patients with severe sepsis, including 259 patients with pre-existing diabetes, were included. Median blood glucose levels were approximately 140 mg/dL at 0 and 72 h indicating that blood glucose was moderately controlled. The rate of initial and late hyperglycemia was 27.3% and 21.7%, respectively. The rate of early hypoglycemic episodes during the initial 24 h was 13.2%. Glycemic control was accompanied by a higher percentage of initial and late hyperglycemia but not with early hypoglycemic episodes, suggesting that glycemic control was targeted at excess hyperglycemia. In nondiabetic patients, late hyperglycemia (hazard ratio, 95% confidence interval; P value: 1.816, 1.116-2.955, 0.016) and early hypoglycemic episodes (1.936, 1.180-3.175, 0.009) were positively associated with in-hospital mortality. Further subgroup analysis suggested that late hyperglycemia and early hypoglycemic episodes independently, and probably synergistically, affect the outcomes. In diabetic patients, however, these correlations were not observed. In conclusion, a significantly high incidence of dysglycemia was observed in our sepsis cohort under moderate glycemic control. Late hyperglycemia in addition to early hypoglycemia was associated with poor outcomes at least in nondiabetic patients. More sophisticated approaches are necessary to reduce the incidence of these serious complications.

The aim of this study was to describe epidemiologic features of pediatric blunt renal trauma. We performed a retrospective analysis using the Japan Trauma Data Bank over 15 years. We included patients younger than 18 years with blunt renal trauma. We analyzed temporal trends and variations across age groups in patient characteristics, intervention, and in-hospital mortality. We also assessed factors associated with in-hospital mortality. We identified 435 pediatric patients with blunt renal trauma. Their median age was 14 years and median Injury Severity Score (ISS) was 17. The most common mechanism of injury was traffic accident in all age groups. Nephrectomy was performed in 3.2%, and the overall in-hospital mortality was 4.6%, both of which showed decreasing trends. The most common mechanism of injury by age group was a pedestrian accident in infants/toddlers/preschoolers (43.5%), pedestrian accident in middle childhood (18.5%), bicycle accident in young teens (24.7%), and motorcycle accident in teenagers (41.2%). Sports-related injury was common in young teens (23.3%) and teenagers (15.2%). Factors such as ISS, shock, concomitant injury, and nephrectomy were associated with high in-hospital mortality. We described decreasing trends in nephrectomy and in-hospital mortality in pediatric blunt renal trauma and found traffic accident and sports-related injury were common in the pediatric population in Japan.

Blunt trauma is a potentially life-threatening injury that requires prompt diagnostic examination and therapeutic intervention. Nevertheless, how impactful a rapid response time is on mortality or functional outcomes has not been well-investigated. This study aimed to evaluate effects of earlier door-to-computed tomography time (D2CT) and door-to-bleeding control time (D2BC) on clinical outcomes in severe blunt trauma. This was a single-center, retrospective cohort study of patients with severe blunt trauma (Injury Severity Score &gt, 16). To assess the effect of earlier D2CT and D2BC on clinical outcomes, we conducted multivariable regression analyses with a consideration for nonlinear associations. Among 671 patients with severe blunt trauma who underwent CT scanning, 163 patients received an emergency bleeding control procedure. The median D2CT and D2BC were 19 min and 57 min, respectively. In a Cox proportional hazard regression model, earlier D2CT was not associated with improved 28-day mortality (p = 0.30), but it was significantly associated with decreased mortality from exsanguination (p = 0.003). Earlier D2BC was significantly associated with improved 28-day mortality (p = 0.026). In conclusion, earlier time to a hemostatic procedure was independently associated with decreased mortality. Meanwhile, time benefits of earlier CT examination were not observed for overall survival but were observed for decreased mortality from exsanguination.

Aim The quick Sequential Organ Failure Assessment (qSOFA) was proposed for use as a simple screening tool for sepsis. In this study, we evaluated the relationship between the prehospital use of qSOFA and prognosis in patients with sepsis or suspected sepsis using the population‐based Osaka Emergency Information Research Intelligent Operation Network (ORION) registry, which compiles prehospital ambulance data and in‐hospital information. Methods The study enrolled 437,974 patients in the ORION registry from January 1 to December 31, 2016. We selected hospitalized patients with sepsis or suspected sepsis using the appropriate codes from the International Classification of Diseases revision 10. We excluded patients with: (i) missing data (outcome, Japan Coma Scale, respiratory rate, and blood pressure); (ii) respiratory rate ≥60/min; and (iii) blood pressure ≥250 mmHg. These measures were evaluated by ambulance personnel when they first contacted the patient in the prehospital setting. The primary end‐point was discharge to death. Results In total, 12,646 patients (median age, 78 [interquartile range, 65–85] years; male, n = 6,760 [53.5%]) were eligible for our analysis. In a multivariable logistic regression analysis adjusted for confounding factors, the proportion of patients discharged to death was significantly higher for those evaluated as qSOFA positive (≥2 points) than qSOFA negative (≤1 point) (265/2,250 [11.78%] vs. 415/10,396 [3.99%]; adjusted odds ratio 2.91; 95% confidence interval, 2.47–3.43; P, In 2016, the quick Sequential Organ Failure Assessment (qSOFA) was proposed for use as a simple index for sepsis. From an analysis of the population‐based ORION registry in Osaka, Japan, our study revealed that the proportion of patients discharged to death was significantly higher in those with sepsis or suspected sepsis evaluated as qSOFA positive versus negative by emergency medical service personnel in the prehospital setting.

Trauma patients die from massive bleeding due to disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype in the early phase, which transforms to DIC with a thrombotic phenotype in the late phase of trauma, contributing to the development of multiple organ dysfunction syndrome (MODS) and a consequently poor outcome. This is a sub-analysis of a multicenter prospective descriptive cross-sectional study on DIC to evaluate the effect of a DIC diagnosis on the survival probability and predictive performance of DIC scores for massive transfusion, MODS, and hospital death in severely injured trauma patients. A DIC diagnosis on admission was associated with a lower survival probability (Log Rank P

Diagnosing blast-induced mild traumatic brain injury (mTBI) is difficult due to minimal imaging findings. This study aimed to establish a rat model of behavioral abnormality caused by blast-induced mTBI and detect new findings for therapeutic intervention.We used a bench-top blast wave generator with the blast wave exiting through a 20-mm I.D. nozzle aimed at the focused target. The blast wave was directed at the head of male Wistar rats under general anesthesia positioned prone 2.5 cm below the nozzle. Peak shock wave pressure was 646.2 ± 70.3 kPa.After blast injury, mTBI rats did not show the findings of brain hemorrhage or contusion macroscopically and on hematoxylin-eosin-stained frozen sections but did show anorexia and weight loss in the early post-injury phase. Behavioral experiments revealed short-term memory impairment at 2 weeks and depression-like behavior at 2 and 6 weeks. Diffusion-weighted ex vivo MRI showed high-intensity areas in layers of the bilateral hippocampus. Immunohistochemical analysis revealed accumulation of reactive microglia and GFAP-positive astrocytes in the same region and loss of NeuN-positive neurons in the hippocampal pyramidal cell layer.This model can reflect the pathophysiology of blast-induced mTBI and could potentially be used to develop therapeutic interventions in the future.

Aim Self‐inflicted injury, as one reason to visit the emergency department, is an important issue in emergency medicine around the world. However, the impact of changes in social systems, such as medical reimbursement revision, on ambulance transport for self‐inflicted injury remains unclear. The aim of this study was to assess the impact of medical reimbursement revision on the emergency transport of self‐inflicted injury patients using nationwide ambulance records. Methods This was a retrospective observational study from April 2012 to March 2016. We analyzed nationwide ambulance records in Japan, and included self‐inflicted injury, drug poisoning, and drug overdose patients transported to hospitals by ambulance. The primary outcome of this study was age‐adjusted number of self‐inflicted injury patients transported by ambulance in each month per 1 million standard populations. To assess the impact of the medical reimbursement revision in 2014, we calculated the R 2, regression coefficients and 95% confidence interval (CI) using interrupted time series analysis. Results This study included 148,873 patients. The R 2 for the interrupted time series model was 0.821. The regression coefficient for the time trend before the medical reimbursement revision was 0.167 (95% CI, 0.090 to 0.244; p, This retrospective observational study assessed the impact of medical reimbursement revision about emergency transport of self‐inflicted injury by ambulance and restriction of prescriptions of multiple psychiatric drugs with interrupted time series analysis. In this study, we revealed that this medical reimbursement revision helped to decrease the number of patients with self‐inflicted injury transported to hospitals by ambulance.

Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory mediators that protect against acute inflammation. Current evidence suggests that BMMNC transplantation can reduce acute tissue injury caused by systemic inflammation and lung dysfunction. This study evaluated the role of BMMNCs in reducing systemic inflammatory responses to vascular endothelial injury in sepsis. Bone marrow cells were harvested from the tibias and femurs of 12-week-old male Wistar rats; BMMNCs were separated by density centrifugation. Additional rats underwent cecal ligation and puncture (CLP) or similar sham surgery. BMMNCs were injected intravenously 30 min after CLP. The Sham and CLP Control groups were administered PBS. The 7-day survival rate improved markedly in the CLP-BMMNC group compared with that in the Control group. BMMNCs markedly suppressed the serum levels of pro-inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and histone H3 at 3, 6, and 12 h after CLP. In the CLP-BMMNC group, the serum levels of syndecan-1, the main component of the vascular endothelial glycocalyx layer, were notably lower than those in the Control group 6 h after CLP. Histological analysis revealed improvement of morphological damages in the CLP-BMMNC group. Ultrastructural analysis revealed that the glycocalyx structure was maintained and the continuity of the vascular endothelial glycocalyx layer was preserved in the BMMNC group, compared with the case for the Control group at 6 and 12 h. Therefore, BMMNC transplantation may provide reduced systemic inflammation and endothelial glycocalyx damage, dramatically improving the survival of rats. These findings provide insights into formulating potential therapeutic strategies against sepsis.

Background: Trauma patients die from massive bleeding due to DIC with a fibrinolytic phenotype in the early phase, which transforms to DIC with a thrombotic phenotype in the late phase of trauma, contributing to the development of MODS and a consequent poor outcome. The aim of this study is to evaluate the effect of a disseminated intravascular coagulation (DIC) diagnosis on the survival probability and predictive performance of DIC scores for massive transfusion, multiple organ dysfunction syndrome (MODS), and hospital death in severely injured trauma patients.Methods: Severely injured adult patients (Injury Severity Score >16) were prospectively evaluated for their DIC scores and molecular markers of coagulation and fibrinolysis immediately after emergency department presentation (0 h) and 3 h after admission. Organ dysfunction was assessed by the sequential organ failure assessment (SOFA) score at 24 h after admission. The performance of DIC scores in predicting massive transfusion, MODS, and hospital death, and the effect of a DIC diagnosis on the survival probability were investigated.Results: The 276 enrolled patients included 121 DIC and 155 non-DIC patients. DIC patients showed larger transfusion volume and higher SOFA scores than non-DIC patients at 24 h after admission. A DIC diagnosis on admission was associated with a lower survival probability (Log Rank ppConclusions: A DIC diagnosis on admission was associated with a low survival probability. DIC scores obtained immediately after trauma predicted a poor prognosis of severely injured trauma patients.Trial registration: UMIN-CTR, UMIN000019588. Registered on 16 November 2015.

The hybrid emergency room (ER) system is a novel trauma workflow that uses angio-computed tomography equipment in a trauma resuscitation room. Although the hybrid ER system decreases time to start surgery and endovascular treatments and improves mortality, the optimal target benefitting from this system remained unclear. We aimed to identify a subset of trauma patients likely to receive the greatest benefits from the hybrid ER.This retrospective cohort study was conducted in a tertiary hospital in Japan from August 2007 to January 2020. We consecutively included severe adult blunt trauma patients (Injury Severity Score [ISS], ≥16) and divided them into two groups: conventional group (August 2007 to July 2011) and hybrid ER (August 2011 to January 2020) group. We evaluated the association between the hybrid ER group and 28-day mortality using multivariable logistic regression analysis. The 28-day mortality trend during the study period was evaluated with restricted cubic spline analysis. To evaluate heterogeneity of effects within various patient severities, we evaluated whether the patients' ISS modified the effect of the hybrid ER on survival.Among 1,050 trauma patients, the conventional group comprised 360 patients and the hybrid ER group comprised 690 patients. Injury Severity Score and probability of survival (Ps) were not significantly different between the groups. Twenty-eight-day mortality was significantly lower in the hybrid ER group (Ps-adjusted odds ratio, 0.48; 95% confidence interval, 0.32-0.71; p0.001). Restricted cubic spline analysis revealed that Ps-adjusted 28-day mortality sharply decreased approximately 200 days after installation of the hybrid ER. Increase of survival probabilities according to the increase of ISS was significantly improved in hybrid ER group (p = 0.014). Because ISS increased to25, survival probabilities in the hybrid ER group were higher compared with those in the conventional group.The hybrid ER may improve posttraumatic mortality, especially in patients with higher baseline severity.Therapeutic/care management, level IV.

In this study, we merged the telephone triage data set with the ORION data set and revealed the profile and outcome of patients transported by ambulance after telephone triage. Most of the patients who were transported by ambulance after telephone triage returned home after visiting the emergency department, and cerebral infarction was the most common diagnosis among the patients who were hospitalized., Aim Details such as diagnosis and outcome of patients transported by ambulance after telephone triage have not been fully revealed. The aim of this study was to reveal profile and outcome about patients transported by ambulance via telephone triage with dataset of telephone triage and population‐based registry for emergency patients. Methods This retrospective descriptive study with a one‐year study period from January 1, 2016 to December 31, 2016 included patients selected from the telephone triage dataset who were transported by ambulance. Key parameters such as age, sex and date and time of ambulance dispatch were used to identify patient data from the ORION registry. We assessed the profile and outcome of the patients in a descriptive epidemiological analysis. Results We included 4,293 patients in the selected datasets whose data were merged, of whom 2,998 patients (69.8%) returned home from the emergency department, 1,255 (29.2%) were hospitalized, 32 (0.7%) were transferred to other hospitals, and 8 (0.2%) died. The most common diagnosis in the emergency departments was “infectious gastroenteritis and colitis, unspecified [A09] (219, 5.1%)”. Among the 1,255 hospitalized patients, 905 patients (72.1%) were discharged home, 254 patients (20.2%) remained hospitalized, 52 patients (4.1%) were transferred to other hospitals, 38 patients (3.0%) died, and 5 patients (0.5%) had missing data. The most common diagnosis was “cerebral infarction [I63.0‐I63.9] (138, 11.0%)”. Conclusion This study revealed the profile and outcome of patients transported by ambulance after telephone triage.

Purpose The aim of this study was to assess the effect of fluid administration by emergency life-saving technicians (ELST) on the prognosis of traffic accident patients by using a propensity score (PS)-matching method. Methods The study included traffic accident patients registered in the JTDB database from January 2016 to December 2017. The main outcome was hospital mortality, and the secondary outcome was cardiopulmonary arrest on hospital arrival (CPAOA). To reduce potential confounding effects in the comparisons between two groups, we estimated a propensity score (PS) by fitting a logistic regression model that was adjusted for 17 variables before the implementation of fluid administration by ELST at the scene. Results During the study period, 10,908 traffic accident patients were registered in the JTDB database, and we included 3502 patients in this study. Of these patients, 142 were administered fluid by ELST and 3360 were not administered fluid by ELST. After PS matching, 141 patients were selected from each group. In the PS-matched model, fluid administration by ELST at the scene was not associated with discharge to death (crude OR: 0.859 [95% CI, 0.500–1.475]; p = 0.582). However, the fluid group showed statistically better outcome for CPAOA than the no fluid group in the multiple logistic regression model (adjusted OR: 0.231 [95% CI, 0.055–0.967]; p = 0.045). Conclusion In this study, fluid administration to traffic accident patients by ELST was associated not with hospital mortality but with a lower proportion of CPAOA.

Current research regarding the association between body mass index (BMI) and altered clinical outcomes of sepsis in Asian populations is insufficient. We investigated the association between BMI and clinical outcomes using two Japanese cohorts of severe sepsis (derivation cohort, Chiba University Hospital, n = 614; validation cohort, multicenter cohort, n = 1561). Participants were categorized into the underweight (BMI p = 0.060). In the primary analysis, multivariate analysis adjusted for baseline imbalance revealed that patients in the underweight group had a significantly increased 28-day mortality compared to those in the non-underweight group (p = 0.031, adjusted odds ratio [OR] 1.91, 95% confidence interval [CI] 1.06–3.46). In a repeated analysis using a multicenter validation cohort (underweight n = 343, non-underweight n = 1218), patients in the underweight group had a significantly increased 28-day mortality compared to those in the non-underweight group (p = 0.045, OR 1.40, 95% CI 1.00–1.97). In conclusion, patients with a BMI

Supplemental Digital Content is available in the text, This study aimed to identify prognostic factors for severe sepsis-related in-hospital mortality using the structural equation model (SEM) analysis with statistical causality. Sepsis data from the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma study (FORECAST), a multicenter cohort study, was used. Forty seven observed variables from the database were used to construct 4 latent variables. SEM analysis was performed on these latent variables to analyze the statistical causality among these data. This study evaluated whether the variables had an effect on in-hospital mortality. Overall, 1148 patients were enrolled. The SEM analysis showed that the 72-hour physical condition was the strongest latent variable affecting mortality, followed by physical condition before treatment. Furthermore, the 72-hour physical condition and the physical condition before treatment strongly influenced the Sequential Organ Failure Assessment (SOFA) score with path coefficients of 0.954 and 0.845, respectively. The SOFA score was the strongest variable that affected mortality after the onset of severe sepsis. The score remains the most robust prognostic factor and can facilitate appropriate policy development on care.

Introduction Polymyxin B hemoperfusion (PMX-HP) is an adjuvant therapy for sepsis or septic shock that removes circulating endotoxin. However, PMX-HP has seldom achieved expectations in randomized trials targeting nonspecific overall sepsis patients. If used in an optimal population, PMX-HP may be beneficial. This study aimed to identify the optimal population for PMX-HP in patients with septic shock. Methods We used a prospective nationwide cohort targeting consecutive adult patients with severe sepsis (Sepsis-2) in 59 intensive care units in Japan. Associations between PMX-HP therapy and in-hospital mortality were assessed using multivariable Cox proportional hazard regression models. To identify best targets for PMX-HP, we developed a non-linear restricted cubic spline model including two-way interaction term (treatment × Acute Physiology and Chronic Health Evaluation [APACHE] II score/Sequential Organ Failure Assessment [SOFA] score) and three-way interaction term (treatment × age × each score). Results The final study cohort comprised 741 sepsis patients (92 received PMX-HP, 625 did not). Cox proportional hazards regression model adjusted for the covariates suggested no association between PMX-HP therapy and improved mortality overall. Effect modification of PMX-HP by APACHE II score was statistically significant (P for interaction = 0.189) but non-significant for SOFA score (P for interaction = 0.413). Three-way interaction analysis revealed suppressed risk hazard in the PMX-HP group versus control group only in septic shock patients with high age and in the most severe subset of both scores, whereas increased risk hazard was observed in those with high age but in the lower severity subset of both scores. Conclusions Our results suggested that although PMX-HP did not reduce in-hospital mortality among overall septic shock patients, it may benefit a limited population with high age and higher disease severity.

Background Dysglycemia is frequently observed in patients with sepsis. However, the relationship between dysglycemia and outcome is inconsistent. We evaluate the clinical characteristics, glycemic abnormalities, and the relationship between the initial glucose level and mortality in patients with sepsis. Methods This is a retrospective sub-analysis of a multicenter, prospective cohort study. Adult patients with severe sepsis (Sepsis-2) were divided into groups based on blood glucose categories (

Aim Combined detailed analysis of patient characteristics and treatment as well as bacterial virulence factors, which all play a central role in the cause of infections leading to severe illness, has not been reported. We aimed to describe the patient characteristics (Charlson comorbidity index [CCI]), treatment (3-h bundle), and outcomes in relation to bacterial virulence of Streptococcus pneumoniae and beta-hemolytic Streptococcus (BHS). Methods This sepsis primary study is part of the larger Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) study, a multicenter, prospective cohort study. We included patients diagnosed with S. pneumoniae and BHS sepsis and examined virulence, defining the high-virulence factor as follows: S. pneumoniae serotype 3, 31, 11A, 35F, and 17F; Streptococcus pyogenes, emm 1; Streptococcus agalactiae, III; and Streptococcus dysgalactiae ssp. equisimilis, emm typing pattern stG 6792. Included patients were divided into high and normal categories based on the virulence factor. Results Of 1,184 sepsis patients enrolled in the Japanese Association for Acute Medicine's FORECAST study, 62 were included in the current study (29 cases with S. pneumoniae sepsis and 33 with BHS). The CCI and completion of a 3-h bundle did not differ between normal and high virulence groups. Risk of 28-day mortality was significantly higher for high-virulence compared to normal-virulence when adjusted for CCI and completion of a 3-h bundle (Cox proportional hazards regression analysis, hazard ratio 3.848; 95% confidence interval, 1.108-13.370; P = 0.034). Conclusion The risk of 28-day mortality was significantly higher for patients with high-virulence compared to normal-virulence bacteria.

Background Predisposing conditions and risk modifiers instead of causes and risk factors have recently been used as alternatives to identify patients at a risk of acute respiratory distress syndrome (ARDS). However, data regarding risk modifiers among patients with non-pulmonary sepsis is rare. Methods We conducted a secondary analysis of the multicenter, prospective, Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) cohort study that was conducted in 59 intensive care units (ICUs) in Japan during January 2016–March 2017. Adult patients with severe sepsis caused by non-pulmonary infection were included, and the primary outcome was having ARDS, defined as meeting the Berlin definition on the first or fourth day of screening. Multivariate logistic regression modeling was used to identify risk modifiers associated with ARDS, and odds ratios (ORs) and their 95% confidence intervals were reported. The following explanatory variables were then assessed: age, sex, admission source, body mass index, smoking status, congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, steroid use, statin use, infection site, septic shock, and acute physiology and chronic health evaluation (APACHE) II score. Results After applying inclusion and exclusion criteria, 594 patients with non-pulmonary sepsis were enrolled, among whom 85 (14.3%) had ARDS. Septic shock was diagnosed in 80% of patients with ARDS and 66% of those without ARDS (p = 0.01). APACHE II scores were higher in patients with ARDS [26 (22–33)] than in those without ARDS [21 (16–28), p < 0.01]. In the multivariate logistic regression model, the following were independently associated with ARDS: ICU admission source [OR, 1.89 (1.06–3.40) for emergency department compared with hospital wards], smoking status [OR, 0.18 (0.06–0.59) for current smoking compared with never smoked], infection site [OR, 2.39 (1.04–5.40) for soft tissue infection compared with abdominal infection], and APACHE II score [OR, 1.08 (1.05–1.12) for higher compared with lower score]. Conclusions Soft tissue infection, ICU admission from an emergency department, and a higher APACHE II score appear to be the risk modifiers of ARDS in patients with non-pulmonary sepsis.

Background: Antithrombin and recombinant human thrombomodulin (rhTM) are individually reported to improve survival in sepsis-induced disseminated intravascular coagulation (DIC). However, continuing controversy exists as to which agent is superior and whether concomitant therapy is superior to individual administration. Methods: This post hoc analysis included adult patients with sepsis-induced DIC from a nationwide multicenter registry database in Japan. We categorized patients into 4 groups: patients who received (1) individual administration of antithrombin, (2) individual administration of rhTM, (3) both, and (4) neither. In-hospital mortality was compared between every 2 groups among the 4 groups by Cox proportional hazards model adjusted with propensity scores. Results: In total, 1432 patients with sepsis-induced DIC were included. Although both antithrombin and rhTM were associated better outcome compared with no anticoagulants, mortality benefits were similar between each individual anticoagulant. Similarly, no significant difference in mortality was detected between individual administrations and concomitant therapy. Conclusion: Antithrombin and rhTM might have comparable efficacy in reducing mortality in patients with sepsis; however, concomitant therapy appeared to offer no additional survival benefit.

Our analysis showed that improved compliance with sepsis bundles was associated with lower in-hospital mortality over a 7-year period in Japan, confirming that the SSC has been executed correctly in our country.

Quick sequential organ failure assessment (qSOFA) was proposed in the new sepsis definition (Sepsis-3). Although qSOFA was created to identify patients with suspected infection and likely to have poor outcomes, the clinical utility of qSOFA to screen sepsis has not been fully evaluated. We investigated the number of patients diagnosed as having severe sepsis who could not be identified by the qSOFA criteria and what clinical signs could complement the qSOFA score. This retrospective analysis of a multicenter prospective registry included adult patients with severe sepsis diagnosed outside the intensive care unit (ICU) by conventional criteria proposed in 2003. We conducted receiver operating characteristic (ROC) analyses to assess the predictive value for in-hospital mortality and compared clinical characteristics between survivors and non-survivors with qSOFA score ≤ 1 point (qSOFA-negative). Among 387 eligible patients, 63 (16.3%) patients were categorized as qSOFA-negative, and 10 (15.9%) of these patients died. The area under the ROC curve for the qSOFA score was 0.615, which was superior to that for the systemic inflammatory response syndrome score (0.531, P = 0.019) but inferior to that for the SOFA score (0.702, P = 0.005). Multivariate logistic regression analysis showed that hypothermia might be associated with poor outcome independently of qSOFA criteria. Our findings suggested that qSOFA had a suboptimal level of predictive value outside the ICU and could not identify 16.3% of patients who were once actually diagnosed with sepsis. Hypothermia might be associated with an increased risk of death that cannot be identified by qSOFA.

To evaluate the efficacy and safety of direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) therapy in patients with sepsis.A systematic review and meta-analysis of four major databases: Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, and Science Citation Index Expanded.Randomized controlled trials comparing PMX-DHP with conventional therapy on the outcome of mortality in patients with severe sepsis/septic shock.Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. Primary outcomes were mortality and adverse events. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate quality of evidence and grade the strength of recommendation.In seven trials enrolling 841 patients, assessment for risk of bias indicated variations in study quality from high (n = 4) to unclear (n = 3) resulting from a lack of adequate randomization, blinding, and incomplete outcomes. Polymyxin B-immobilized fiber therapy was associated with lower mortality (risk ratio, 0.65; 95% confidence interval [CI], 0.47-0.89; p = 0.007; IPolymyxin B-immobilized fiber therapy was associated with reduced mortality in sepsis/septic shock. Based on the low quality of evidence, therapeutic use of PMX-DHP for survival benefit may be recommended conditionally for patients with high risk of death. Additional large randomized controlled trials are needed to confirm or refute this evidence.

Selecting an appropriate target population is essential to maximize survival benefits of anticoagulant therapy against sepsis. Our meta-analysis of three populations with sepsis and nationwide observational study in Japan showed that anticoagulants improved mortality only in sepsis-induced disseminated intravascular coagulation (DIC) but not in non-DIC. This divergent effect was physiologically explained by host-protective immune responses of local thrombosis, which are mandatory in the early stage of sepsis. Meanwhile, the lack of definitive evidence for survival benefit provided by several trials of sepsis-induced DIC indicated that this condition was probably not the best target of anticoagulants. Our multicenter cohort study including only patients with sepsis-induced DIC showed a survival benefit from recombinant thrombomodulin only in patients with high disease severity. Thus, we believe that the population with sepsis and DIC and high disease severity is the optimal target for anticoagulant therapy. Anticoagulant therapy without appropriate target selection should be avoided because of the increased risk of bleeding with no survival benefit.