Current Clinical Practice of Laboratory Testing of the Hemostasis and Coagulation System in Patients with Sepsis: A Nationwide Observational Study in Japan.

Introduction: The clinical benefit of hemostasis molecular indicators such as thrombin-antithrombin complex (TAT), soluble fibrin (SF), and prothrombin fragment 1 + 2 (F1+2) for the diagnosis of disseminated intravascular coagulation (DIC) is reported. Recently, novel DIC diagnostic criteria that adopt them were proposed in Japan. Despite the theoretical understanding of their function, the practical use of these markers remains unclear. The present study aimed to provide a descriptive overview of current clinical practice regarding the measurement of hemostasis markers in sepsis management in Japan. Methods: This retrospective observational analysis used the Japanese Diagnosis Procedure Combination inpatient database containing data from more than 1500 acute-care hospitals in Japan. We identified adult patients hospitalized for sepsis between April 2018 and March 2021. Descriptive statistics for measuring several hemostasis laboratory markers were summarized using patient disease characteristics, hospital characteristic, and geographical location. Results: This study included 153,474 adult sepsis patients. Crude in-hospital mortality was 30.0%. Frequency of measurement of fibrinogen, fibrin degradation products (FDP), and D-dimer in sepsis patients on admission was 43.2%, 36.1%, and 46.4%, respectively. Novel and specific hemostasis molecular markers such as TAT, SF, and F1+2 were seldom measured (1.9%, 1.7%, and 0.02%, respectively). Hemostasis molecular markers were more frequently measured with progression of thrombocytopenia. Measurement of these clinically favorite hemostasis markers was influenced not only by disease characteristics but also hospital characteristic or geographical location. Conclusions: Hemostasis molecular markers such as TAT, SF, and F1+2 were rarely measured in clinical settings. Although adopted by several DIC scoring systems, neither fibrinogen, FDP, nor D-dimer was routinely measured.

Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.

BACKGROUND: Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES: To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS: We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS: Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION: JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

External Validation of Updated Prediction Models for Neurological Outcomes at 90 Days in Patients With Out-of-Hospital Cardiac Arrest.

BACKGROUND: Few prediction models for individuals with early-stage out-of-hospital cardiac arrest (OHCA) have undergone external validation. This study aimed to externally validate updated prediction models for OHCA outcomes using a large nationwide dataset. METHODS AND RESULTS: We performed a secondary analysis of the JAAM-OHCA (Comprehensive Registry of In-Hospital Intensive Care for Out-of-Hospital Cardiac Arrest Survival and the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest) registry. Previously developed prediction models for patients with cardiac arrest who achieved the return of spontaneous circulation were updated. External validation was conducted using data from 56 institutions from the JAAM-OHCA registry. The primary outcome was a dichotomized 90-day cerebral performance category score. Two models were updated using the derivation set (n=3337). Model 1 included patient demographics, prehospital information, and the initial rhythm upon hospital admission; Model 2 included information obtained in the hospital immediately after the return of spontaneous circulation. In the validation set (n=4250), Models 1 and 2 exhibited a C-statistic of 0.945 (95% CI, 0.935-0.955) and 0.958 (95% CI, 0.951-0.960), respectively. Both models were well-calibrated to the observed outcomes. The decision curve analysis showed that Model 2 demonstrated higher net benefits at all risk thresholds than Model 1. A web-based calculator was developed to estimate the probability of poor outcomes (https://pcas-prediction.shinyapps.io/90d_lasso/). CONCLUSIONS: The updated models offer valuable information to medical professionals in the prediction of long-term neurological outcomes for patients with OHCA, potentially playing a vital role in clinical decision-making processes.

Efficacy of antithrombin administration for patients with sepsis: A systematic review, meta-analysis, and meta-regression.

Aims: There have been inconsistent reports regarding the effect of antithrombin on sepsis; furthermore, there are limited reports on how dosage affects therapeutic efficacy. Thus, we aimed to perform a systematic review and meta-analysis of the use of antithrombin for sepsis and a meta-regression analysis of antithrombin dosage. Methods: We included randomized controlled trials (RCTs) and observational studies of adult patients with sepsis who received antithrombin. Outcomes included all-cause mortality and serious bleeding complications. Statistical analyses and data synthesis were performed using a random-effects model; further, meta-regression and funnel plots were used to explore heterogeneity and biases. Results: Seven RCTs and six observational studies were included. Most patients in the RCTs and observational studies had severe sepsis and septic-disseminated intravascular coagulation (DIC), respectively. A meta-analysis using RCTs showed no significant differences in mortality between the antithrombin and control groups. However, the meta-analysis of observational studies indicated a trend of decreasing mortality rates with antithrombin administration (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.68-0.92; p = 0.002). Bleeding complications were significantly higher in the antithrombin group than in the control group in both study types (OR, 1.90; 95% CI, 1.52-2.37; p < 0.01). The meta-regression analysis showed no correlation between antithrombin dosage and mortality. Conclusion: A meta-analysis of RCTs confirmed no survival benefit of antithrombin, whereas that of observational studies, which mostly focused on septic DIC, showed a significant beneficial effect on improving outcomes. Indications of antithrombin should be considered based on its beneficial and harmful effects.

A meta-analysis and trial sequential analysis of randomised controlled trials comparing nonoperative and operative management of chest trauma with multiple rib fractures.

BACKGROUND: Operative treatment of traumatic rib fractures for better outcomes remains under debate. Surgical stabilization of rib fractures has dramatically increased in the last decade. This study aimed to perform a systematic review and meta-analysis of randomised controlled trials (RCTs) to assess the effectiveness and safety of operative treatment compared to conservative treatment in adult patients with traumatic multiple rib fractures. METHODS: A systematic literature review was performed according to the preferred reporting items for systematic reviews and meta-analyses guidelines. We searched MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials and used the Cochrane Risk-of-Bias 2 tool to evaluate methodological quality. Relative risks with 95% confidence interval (CI) were calculated for outcomes: all-cause mortality, pneumonia incidence, and number of mechanical ventilation days. Overall certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, with trial sequential analysis performed to establish implications for further research. RESULTS: From 719 records, we included nine RCTs, which recruited 862 patients. Patients were assigned to the operative group (received surgical stabilization of chest wall injury, n = 423) or control group (n = 439). All-cause mortality was not significantly different (RR = 0.53; 95% CI 0.21 to 1.38, P = 0.35, I2 = 11%) between the two groups. However, in the operative group, duration of mechanical ventilation (mean difference -4.62; 95% CI -7.64 to -1.60, P < 0.00001, I2 = 94%) and length of intensive care unit stay (mean difference -3.05; 95% CI -5.87 to -0.22; P < 0.00001, I2 = 96%) were significantly shorter, and pneumonia incidence (RR = 0.57; 95% CI 0.35 to 0.92; P = 0.02, I2 = 57%) was significantly lower. Trial sequential analysis for mortality indicated insufficient sample size for a definitive judgment. GRADE showed this meta-analysis to have very low to low confidence. CONCLUSION: Meta-analysis of large-scale trials showed that surgical stabilization of multiple rib fractures shortened the duration of mechanical ventilation and reduced the incidence of pneumonia but lacked clear evidence for improvement of mortality compared to conservative treatment. Trial sequential analysis suggested the need for more cases, and GRADE highlighted low certainty, emphasizing the necessity for further targeted RCTs, especially in mechanically ventilated patients. SYSTEMATIC REVIEW REGISTRATION: UMIN Clinical Trials Registry UMIN000049365.

A systematic review and meta-analysis of recombinant human soluble thrombomodulin for the treatment of DIC associated with hematological malignancies.

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) is commonly used in Japan to treat disseminated intravascular coagulation (DIC), but its efficacy compared with other anticoagulants is unclear. We conducted a systematic review and meta-analysis to investigate this issue in DIC patients with hematological malignancies. METHODS: We searched PubMed, Cochrane, and Scopus for prospective and retrospective studies evaluating the efficacy and safety of rhTM in DIC patients with hematological malignancies between April 2008 and April 2023. We performed a systematic review and meta-analysis evaluating recovery from DIC, hemorrhagic adverse events (AEs), and overall survival (OS). RESULTS: We analyzed one prospective (64 patients) and seven retrospective studies (209 patients). Use of rhTM was associated with a higher rate of recovery from DIC (OR: 2.25 [1.09-4.63] and 1.98 [1.12-3.50] in prospective and retrospective studies, respectively; same order below) and fewer hemorrhagic AEs (OR: 0.83 [0.30-2.30] and 0.21 [0.08-0.57]). rhTM did not improve OS (OR: 1.06 [0.42-2.66] and 1.72 [0.87-3.39]), although the incidence of hemorrhagic death was lower in the rhTM group (0 of 94 patients). CONCLUSION: Use of rhTM in patients with hematological malignancy-associated DIC is strongly expected to be effective and safe.

Effects of combination therapy of antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis.

BACKGROUND: Disseminated intravascular coagulation (DIC) syndrome is a highly lethal condition characterized by the complication of multiple organ damage. Although the effects of combined antithrombin (AT) and recombinant thrombomodulin (rTM) on DIC syndrome have previously been examined, the results are inconsistent and inconclusive. Therefore, we conducted a systematic review on the combined administration of AT and rTM for the treatment of septic DIC to investigate the superiority of the combination therapy over either AT or rTM monotherapy using a random-effects analysis model. METHOD: We searched electronic databases, including Medline, Cochrane Central Register of Controlled Trials, Scopus, and Igaku-Chuo Zasshi (ICHU-SHI) Japanese Central Review of Medicine Web from inception to January 2022. Studies assessing the efficacy of combined AT and rTM were included. The primary outcome was all-cause mortality, and the secondary outcome was occurrence of serious bleeding complications compared to monotherapy. We presented the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI) depending on reporting results in each primary study. RESULTS: We analyzed seven enrolled clinical trials, all of which were observational studies. Combination therapy had a non-significant favorable association with lower 28-day mortality compared to monotherapy (HR 0.67 [0.43-1.05], OR 0.73 [0.45-1.18]). The I2 values were 60% and 72%, respectively, suggesting high heterogeneity. As a secondary outcome, bleeding complications were similar between the two groups (pooled OR 1.11 [0.55-2.23], I2 value 55%). CONCLUSIONS: Although the findings in this analysis could not confirm a statistically significant effect of AT and rTM combination therapy for septic DIC, it showed a promising effect in terms of improving mortality. The incidence of bleeding was low and clinically feasible. Further research is warranted to draw more conclusive results. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: 000049820).

Relationship between critical care nutrition and post-intensive care syndrome in surviving ventilated patients with COVID-19: a multicenter prospective observational study.

The impact of nutrition therapy in the acute phase on post-intensive care syndrome (PICS) remains unclear. We conducted a multicenter prospective study on adult patients with COVID-19 who required mechanical ventilation for more than three days. The questionnaire was mailed after discharge. Physical PICS, defined as less than 90 points on the Barthel index (BI), was assigned as the primary outcome. We examined the types of nutrition therapy in the first week that affected PICS components. 269 eligible patients were evaluated 10 months after discharge. Supplemental parenteral nutrition (SPN) >400 kcal/day correlated with a lower occurrence of physical PICS (10% vs 21.92%, p = 0.042), whereas the amounts of energy and protein provided, early enteral nutrition, and a gradual increase in nutrition delivery did not, and none correlated with cognitive or mental PICS. A multivariable regression analysis revealed that SPN had an independent impact on physical PICS (odds ratio 0.33, 95% CI 0.12-0.92, p = 0.034), even after adjustments for age, sex, body mass index and severity. Protein provision ≥1.2 g/kg/day was associated with a lower occurrence of physical PICS (odds ratio 0.42, 95% CI 0.16-1.08, p = 0.071). In conclusion, SPN in the acute phase had a positive impact on physical PICS for ventilated patients with COVID-19.

Understanding the pathophysiology of acute critical illness: translational lessons from zebrafish models.

The models used to investigate the pathophysiological mechanisms of acute critical illness are not limited to mammalian species. The zebrafish (Danio rerio) is a popular model organism for studying diseases due to its transparency and rapid development. The genes and signaling pathways involved in acute critical illness appear highly conserved among zebrafish and humans. Forward genetics such as random mutagenesis by a chemical mutagen or reverse genetics methods represented by CRISPR/Cas9 allowed researchers to reveal multiple novel aspects of pathological processes in areas including infection, immunity, and regeneration. As a model of sepsis, transgenic zebrafish allowed the visualization of lipopolysaccharide (LPS)-induced vascular leakage in vivo and the demonstration of changes in the expression of cellular junction proteins. Other transgenic zebrafish visualizing the extravascular migration of neutrophils and macrophages have demonstrated a decrease in neutrophil numbers and an increased expression of an inflammatory gene, which replicates a phenomenon observed in humans in clinically encountered sepsis. The regenerative potential and the visibility of zebrafish organs also enabled clarification of important mechanisms in wound healing, angiogenesis, and neurogenesis. After spinal cord injury (SCI), a marker gene expressed in glial bridging was discovered. Furthermore, localized epithelial-to-mesenchymal transition (EMT) and molecular mechanisms leading to spinal cord repair were revealed. These translational studies using zebrafish show the potential of the model system for the treatment of acute critical illnesses such as sepsis, organ failure, and trauma.

COAGULOPATHY PARAMETERS PREDICTIVE OF OUTCOMES IN SEPSIS-INDUCED ACUTE RESPIRATORY DISTRESS SYNDROME: A SUBANALYSIS OF THE TWO PROSPECTIVE MULTICENTER COHORT STUDIES.

ABSTRACT: Background: Although coagulopathy is often observed in acute respiratory distress syndrome (ARDS), its clinical impact remains poorly understood. Objectives: This study aimed to clarify the coagulopathy parameters that are clinically applicable for prognostication and to determine anticoagulant indications in sepsis-induced ARDS. Method: This study enrolled patients with sepsis-derived ARDS from two nationwide multicenter, prospective observational studies. We explored coagulopathy parameters that could predict outcomes in the Focused Outcome Research on Emergency Care for Acute Respiratory Distress Syndrome, Sepsis, and Trauma (FORECAST) cohort, and the defined coagulopathy criteria were validated in the Sepsis Prognostication in Intensive Care Unit and Emergency Room-Intensive Care Unit (SPICE-ICU) cohort. The correlation between anticoagulant use and outcomes was also evaluated. Results: A total of 181 patients with sepsis-derived ARDS in the FORECAST study and 61 patients in the SPICE-ICU study were included. In a preliminary study, we found the set of prothrombin time-international normalized ratio ≥1.4 and platelet count ≤12 × 10 4 /µL, and thrombocytopenia and elongated prothrombin time (TEP) coagulopathy as the best coagulopathy parameters and used it for further analysis; the odds ratio (OR) of TEP coagulopathy for in-hospital mortality adjusted for confounding was 3.84 (95% confidence interval [CI], 1.66-8.87; P = 0.005). In the validation cohort, the adjusted OR for in-hospital mortality was 32.99 (95% CI, 2.60-418.72; P = 0.002). Although patients without TEP coagulopathy showed significant improvements in oxygenation over the first 4 days, patients with TEP coagulopathy showed no significant improvement (ΔPaO 2 /FiO 2 ratio, 24 ± 20 vs. 90 ± 9; P = 0.026). Furthermore, anticoagulant use was significantly correlated with mortality and oxygenation recovery in patients with TEP coagulopathy but not in patients without TEP coagulopathy. Conclusion: Thrombocytopenia and elongated prothrombin time coagulopathy is closely associated with better outcomes and responses to anticoagulant therapy in sepsis-induced ARDS, and our coagulopathy criteria may be clinically useful.

Effect of Inhaled Ciclesonide in Non-Critically Ill Hospitalized Patients With Coronavirus Disease 2019: A Multicenter Observational Study in Japan.

Background: Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic. Although systemic steroids play an important role in treating patients with severe COVID-19, the role of inhaled corticosteroids in non-critically ill, hospitalized patients with COVID-19 remains unclear. Methods: We analyzed findings in non-critically ill, hospitalized patients with COVID-19 who were >18 years old and were admitted to 64 Japanese hospitals between January and September 2020. We performed propensity score matching analysis to evaluate 28-day and in-hospital mortality rates with or without inhaled ciclesonide within 2 days of admission. Sensitivity analyses using inverse probability weighting analysis, and generalized estimating equation method were also performed. Results: Eligible patients (n = 3638) were divided into ciclesonide (n = 290) and control (n = 3, 393) groups. The 1-to-4 propensity score matching analysis included 271 ciclesonide users and 1084 nonusers. There were no significant differences between the 2 groups for 28-day (3.3% vs 2.3%; risk difference, 1.0% [95% confidence interval, -1.2 to 3.3]) or in-hospital (4.8% vs 2.6%; risk difference, 2.2 [-.5 to 4.9]) mortality rates. The sensitivity analysis showed similar outcomes. Conclusions: From this multicenter observational study in Japan, inhaled ciclesonide did not decrease 28-day or in-hospital mortality rates in non-critically ill, hospitalized patients with COVID-19. Future large, multinational, randomized trials are required to confirm our results.

Hyperoxia for sepsis and development of acute lung injury with increased mortality.

BACKGROUND: Supraphysiological oxygen administration causes unfavourable clinical outcomes in various diseases. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with severe infection. METHODS: A post-hoc analysis of a nationwide multicentre prospective observational study on sepsis (SPICE Study) was conducted, including adult patients admitted to the intensive care unit with available arterial partial pressure of oxygen (PaO2) at the treatment initiation for severe infection. Hyperoxia was defined as a PaO2 level of ≥300 mm Hg and in-hospital mortality was compared between patients with and without hyperoxia. RESULTS: Of the 563 patients eligible for the study, 49 had hyperoxia at treatment initiation for severe infection. The in-hospital all-cause mortality rates of patients with and without hyperoxia were 14 (29.2%) and 90 (17.6%), respectively. Inverse probability weighting analyses with propensity scores revealed the association between hyperoxia and increased in-hospital mortality rate (28.8% vs 18.8%; adjusted OR 1.75 (1.03 to 2.97); p=0.038), adjusting for patient demographics, comorbidities, site of infection, severity of infection, haemodynamic and respiratory status, laboratory data and location of patient at infection development. Acute lung injury developed more frequently in patients with hyperoxia on the following days after infection treatment, whereas sepsis-related mortality was comparable regardless of hyperoxia exposure. CONCLUSION: Hyperoxia with PaO2 ≥300 mm Hg at treatment initiation of severe infection was associated with an increased in-hospital mortality rate in patients requiring intensive care. The amount of oxygen to administer to patients with severe infection should be carefully determined. TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry (UMIN000027452).

Associated organs and system with COVID-19 death with information of organ support: a multicenter observational study.

BACKGROUND: The organ dysfunction that is associated with death in COVID-19 patients has not been determined in multicenter epidemiologic studies. In this study, we evaluated the major association with death, concomitant organ dysfunction, and proportion of multiple organ failure in deaths in patients with COVID-19, along with information on organ support. METHODS: We performed an observational cohort study using the Japanese multicenter research of COVID-19 by assembling a real-world data (J-RECOVER) study database. This database consists of data on patients discharged between January 1 and September 31, 2020, with positive SARS-CoV-2 test results, regardless of intensive care unit admission status. These data were collected from the Diagnosis Procedure Combination and electronic medical records of 66 hospitals in Japan. The clinician identified and recorded the organ responsible for the death of COVID-19. RESULTS: During the research period, 4,700 patients with COVID-19 were discharged from 66 hospitals participating in the J-RECOVER study; of which, 272 patients (5.8%) from 47 institutions who died were included in this study. Respiratory system dysfunction (87.1%) was the leading association with death, followed by cardiovascular (4.8%), central nervous (2.9%), gastrointestinal (2.6%), and renal (1.1%) dysfunction. Most patients (96.7%) who died of COVID-19 had respiratory system damage, and about half (48.9%) had multi-organ damage. Of the patients whose main association with death was respiratory dysfunction, 120 (50.6%) received mechanical ventilation. CONCLUSION: This study showed that although respiratory dysfunction was the most common association with death in many cases, multi-organ dysfunction was associated with death due to COVID-19.

Persistent and Late-Onset Disseminated Intravascular Coagulation Are Closely Related to Poor Prognosis in Patients with Sepsis.

BACKGROUND: Septic-associated disseminated intravascular coagulation (DIC) is heterogeneous regarding prognosis and responsiveness to anticoagulant therapy. OBJECTIVES: To investigate the relationship between the timing of development and recovery of DIC, its prognosis, and the difference in response to anticoagulant therapy in sepsis-associated DIC patients. METHODS: This study was performed with a dataset from a multicenter nationwide retrospective cohort study (J-Septic DIC registry) in Japan between 2011 and 2013 to reveal the subgroup "high risk of death in DIC" and investigate the relationship between anticoagulant use and mortality. Patients were assigned to four groups based on the International Society on Thrombosis and Haemostasis-overt DIC status at days 1 and 3: non-DIC (-/-), early-recovered DIC (+/-), late-onset DIC (-/+), and persistent DIC (+/+). RESULTS: A total of 1,922 patients were included. In-hospital mortality in persistent and late-onset DIC patients was significantly higher than in patients with non-DIC and early-recovered DIC. This finding indicates that persistent DIC and late-onset DIC were a poor-prognosis subgroup, "high-risk" DIC. Meanwhile, patients with high-risk DIC treated with anticoagulants had significantly better outcomes than those without anticoagulants after adjusting for confounding factors. CONCLUSION: This study showed that individuals with a high risk of death, persistent DIC, and late-onset DIC were a poor-prognostic subgroup in septic DIC; however, high-risk DIC is also a subgroup that can obtain more benefits from anticoagulant therapy.

Anticoagulant therapies against sepsis-induced disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a frequent but lethal complication in sepsis. Anticoagulant therapies, such as heparin, antithrombin, activated protein C, and recombinant human-soluble thrombomodulin, were expected to regulate the progression of coagulopathy in sepsis. Although a number of randomized controlled trials (RCTs) have evaluated the survival effects of these therapies over the past few decades, there remains no consistent evidence showing a significant survival benefit of anticoagulant therapies. Currently, anticoagulant therapies are not conducted as a standard treatment against sepsis in many countries and regions. However, most of these RCTs were performed overall in patients with sepsis but not in those with sepsis-induced DIC, who were theoretically the optimal target population of anticoagulants. Actually, multiple lines of evidence from observational studies and meta-analyses of the RCTs have suggested that anticoagulant therapies might reduce mortality only when used in septic DIC. In addition, the severity of illness is another essential factor that maximally affects the efficacy of the therapy. Therefore, to provide evidence on the true effect of anticoagulant therapies, the next RCTs must be designed to enroll only patients with sepsis-induced overt DIC and a high severity of illness. To prepare these future RCTs, a novel scientific infrastructure for accurate detection of patients who can receive maximal benefit from anticoagulant therapies also needs to be established.

Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).

Ultrasound stimulation of the vagal nerve improves acute septic encephalopathy in mice.

Septic encephalopathy (SE) is characterized by symptoms such as coma, delirium, and cognitive dysfunction, and effective therapeutic interventions for SE remain elusive. In this study, we aimed to investigate the potential alleviating effects of vagal nerve stimulation (VNS) on SE-associated signs. To evaluate our hypothesis, we utilized a mouse model of SE induced by intraperitoneal injection of lipopolysaccharide (0.3 mg per mouse) and administered noninvasive, high-frequency ultrasound VNS. To assess the efficacy of ultrasound VNS, we measured inflammation-related molecules, including the α7 nicotinic acetylcholine receptor (α7nAChR) expression in peritoneal macrophages and plasma interleukin 1ß (IL-1ß) levels. Consistent with our hypothesis, SE mice exhibited reduced α7nAChR expression in macrophages and elevated IL-1ß levels in the blood. Remarkably, VNS in SE mice restored α7nAChR expression and IL-1ß levels to those observed in control mice. Furthermore, we evaluated the effects of VNS on survival rate, body temperature, and locomotor activity. SE mice subjected to VNS demonstrated a modest, yet significant, improvement in survival rate, recovery from hypothermia, and increased locomotor activity. To investigate the impact on the brain, we examined the hippocampus of SE mice. In control mice, VNS increased the expression of c-fos, a marker of neuronal electrical excitability, in the hippocampus. In SE mice, VNS led to the restoration of aberrant firing patterns in hippocampal neurons. Additionally, proteomic analysis of hippocampal tissue in SE mice revealed abnormal increases in two proteins, tissue factor (TF) and acyl-CoA dehydrogenase family member 9 (ACAD9), which returned to control levels following VNS. Collectively, our findings support the value of exploring the beneficial effects of ultrasound VNS on SE.

Net reclassification index in comparison of prognostic value of disseminated intravascular coagulation diagnostic criteria by Japanese Society on Thrombosis and Hemostasis and International Society on Thrombosis and Haemostasis: a multicenter prospective cohort study.

BACKGROUND: We compared the prognostic value of the Japanese Society on Thrombosis and Hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria with that of the International Society on Thrombosis and Haemostasis (ISTH) DIC diagnostic criteria for 28-day in-hospital mortality. METHODS: We conducted a multicenter prospective cohort study involving two hematology departments, four emergency departments, and one general medicine department in Japan between August 2017 and July 2021. We assessed three ISTH DIC diagnostic criteria categories using low cutoff levels of D-dimer (low D-dimer), high cutoff levels of D-dimer (high D-dimer), and fibrinogen/fibrin degradation products (FDP) as fibrin-related markers. The main outcome was diagnosis-based category additive net reclassification index (NRI). RESULTS: A total of 222 patients were included: 82 with hematopoietic disorders, 86 with infections, and 54 with other diseases. The 28-day in-hospital mortality rate was 14% (n = 31). The DIC rates diagnosed by the JSTH, ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were 52.7%, 47.3%, 42.8%, and 27.0%, respectively. The overall category additive NRI by JSTH DIC diagnosis vs. ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were - 10 (95% confidence interval [CI]: -28 to 8, p = 0.282), - 7.8 (95% CI: -26 to 10, p = 0.401), and - 11 (95% CI: -26 to 3, p = 0.131), respectively. CONCLUSIONS: JSTH criterion showed the highest sensitivity for DIC diagnosis that did not improve but reflected the same prognostic value for mortality evaluated using ISTH DIC diagnosis criteria. This finding may help clinicians to use JSTH DIC criterion as an early intervention strategy in patients with coagulopathy.

Impact of the hybrid emergency department on resuscitation strategies and outcomes in ventricular fibrillation.

BACKGROUND: The Hybrid emergency room (ER) is a novel resuscitation room that includes a whole-body computed tomography scanner and angiography system, which enables physicians to seamlessly conduct resuscitation, diagnosis and therapeutic interventions without patient transfer. This study aimed to assess the impact of the Hybrid ER on mortality in patients with ventricular fibrillation cardiac arrest. METHODS: This was a retrospective cohort study conducted in a tertiary hospital in Japan. We consecutively included adult cardiac arrest patients who were transferred to the emergency departments from January 2007 to May 2020, and were confirmed to be in ventricular fibrillation within 10 min from patient arrival. The study population was divided into two groups: the conventional group (from January 2007 to July 2011) and the Hybrid ER group (from August 2011 to May 2020). The primary endpoint of this study was defined as all-cause in-hospital death. Secondary endpoints included the frequency of extracorporeal cardiopulmonary resuscitation (ECPR) and percutaneous coronary intervention (PCI), and door-to-balloon time and door-to-ECPR time. RESULTS: We included 115 patients in the conventional group and 185 patients in the Hybrid ER group. In-hospital mortality was significantly decreased in the Hybrid ER group (adjusted hazard ratio, 0.79; 95% confidence interval 0.64, 0.97; p = 0.026). Door-to-ECPR time was significantly shorter in the Hybrid ER group (p < 0.001, Gehan-Breslow-Wilcoxon test), as was door-to-balloon time in this group (p = 0.004, Gehan-Breslow-Wilcoxon test). In interrupted time-series analyses, it was visually recognized that the ratio of patients who received ECPR and PCI increased, and door-to-ECPR time and door-to-balloon time were shortened from 2011 to 2012 (before and after installation of the Hybrid ER). CONCLUSION: Installation of the Hybrid ER was associated with a reduced time to ECPR and PCI and with a possible improvement in survival in patients with ventricular fibrillation cardiac arrest.

Association between obesity and mortality in critically ill COVID-19 patients requiring invasive mechanical ventilation: a multicenter retrospective observational study.

This study aimed to determine whether obesity and disease outcomes are associated in patients with critically-ill coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation (IMV). This retrospective observational study using Japanese multicenter registry data included COVID-19 patients who required IMV and were discharged between January and September 2020. The patients were divided into the obese (body mass index [BMI] ≥ 25 kg/m2) and nonobese (BMI < 25 kg/m2) groups. Logistic regression models were used to analyze the association between obesity and disease outcomes. The primary outcome was in-hospital mortality; the secondary outcome was venovenous extracorporeal membrane oxygenation (VV-ECMO) implementation. Altogether, 477 patients were enrolled (obese, n = 235, median BMI, 28.2 kg/m2; nonobese, n = 242, median BMI, 22.4 kg/m2). Obesity was significantly associated with lower in-hospital mortality in the unadjusted logistic regression model (odds ratio 0.63; 95% confidence interval, 0.42-0.97; p = 0.033), but not with mortality in the adjusted logistic regression model using age, sex, and Charlson Comorbidity Index as covariates (p = 0.564). Obesity was not associated with VV-ECMO implementation in both unadjusted and adjusted models (unadjusted, p = 0.074; adjusted, p = 0.695). Obesity was not associated with outcomes in COVID-19 patients requiring IMV. Obesity may not be a risk factor for poor outcomes in these patients.